Bicyclic pyrazole compounds as allosteric modulators of mglur5 receptors

ABSTRACT

In one aspect, the invention relates to bicyclic pyrazole compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 61/421,188,filed Dec. 8, 2010, which is hereby incorporated by reference in theirentirety.

BACKGROUND

Glutamate (L-glutamic acid) is the major excitatory transmitter in themammalian central nervous system, exerting its effects through bothionotropic and metabotropic glutamate receptors. The metabotropicglutamater receptors (mGluRs) belong to family C (also known as family3) of the G-protein-coupled receptors (GPCRs). They are characterized bya seven transmembrane (7TM) α-helical domain connected via a cysteinerich-region to a large bi-lobed extracellular amino-terminal domain(FIG. 1). While the orthosteric binding site is contained in theamino-terminal domain, currently known allosteric binding sites residein the 7TM domain. The mGluR family comprises eight known mGluRsreceptor types (designated as mGluR1 through mGluR8). Several of thereceptor types are expressed as specific splice variants, e.g. mGluR5aand mGluR5b or mGluR8a, mGluR8b and mGluR8c. The family has beenclassified into three groups based on their structure, preferred signaltransduction mechanisms, and pharmacology.

Group I receptors (mGluR1 and mGluR5) are coupled to Gαq, a process thatresults in stimulation of phospholipase C and an increase inintracellular calcium and inositol phosphate levels. Group II receptors(mGluR2 and mGluR3) and group III receptors (mGluR4, mGluR6, mGluR7, andmGluR8) are coupled to Gαi, which leads to decreases in cyclic adenosinemonophosphate (cAMP) levels. While the Group I receptors arepredominately located postsynaptically and typically enhancepostsynaptic signaling, the group II and III receptors are locatedpresynaptically and typically have inhibitory effects onneurotransmitter release. Without wishing to be bound by theory,increasing evidence indicates mGluRs play an important role in lastingchanges in synaptic transmission, and studies of synaptic plasticity inthe Fmr1 knockout mouse have identified a connection between the fragileX phenotype and mGluR signaling.

The identification of small molecule mGluR agonists that bind at theorthosteric site has greatly increased the understanding of the rolesplayed by these receptors and their corresponding relation to disease.Because the majority of these agonists were designed as analogs ofglutamate, they typically lack the desired characteristics for drugstargeting mGluR such as oral bioavailability and/or distribution to thecentral nervous system (CNS). Moreover, because of the highly conservednature of the glutamate binding site, most orthosteric agonists lackselectivity among the various mGluRs.

Selective positive allosteric modulators (“PAMs”) are compounds that donot directly activate receptors by themselves, but binding of thesecompounds potentiates the response of the receptor to glutamate or otherorthosteric agonists by increasing the affinity of an orthostericagonist at the orthosteric binding site. PAMs are thus an attractivemechanism for enhancing appropriate physiological receptor activation.

Unfortunately, there is a scarcity of selective positive allostericmodulators for the mGluR5 receptor. Further, conventional mGluR5receptor modulators typically lack satisfactory aqueous solubility andexhibit poor oral bioavailability. Therefore, there remains a need formethods and compositions that overcome these deficiencies and thateffectively provide selective positive allosteric modulators for themGluR5 receptor.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds useful as positive allosteric modulators (i.e., potentiators)of the metabotropic glutamate receptor subtype 5 (mGluR5), methods ofmaking same, pharmaceutical compositions comprising same, and methods oftreating neurological and psychiatric disorders associated withglutamate dysfunction using same.

Disclosed are compounds having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are compounds having a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

The present invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound as definedherein and a pharmaceutically acceptable carrier or excipient. Alsodisclosed are pharmaceutical compositions comprising a therapeuticallyeffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier.

Furthermore, the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound as described herein.

Also disclosed are synthetic method comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl, and (b) reacting the compound with Ar²COX or (Ar²CO)₂O,wherein X is a leaving group, and wherein Ar² is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar² is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, thereby forming anamide.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein R is hydrogen or alkyl; wherein Ar¹ is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar¹ is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(1a)and R^(1b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; and wherein R² isselected from hydrogen, halogen, cyano, C1-C4 alkyl, monohalo C1-C4alkyl, and polyhalo C1-C4 alkyl, and (b) reacting the compound with:

wherein X is a leaving group; wherein each of R^(4a) and R^(4b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; and wherein R^(4a) and R^(5a) are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl, therebyforming:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein each R is independently hydrogen or alkyl; and wherein R² isselected from hydrogen, halogen, cyano, C1-C4 alkyl, monohalo C1-C4alkyl, and polyhalo C1-C4 alkyl, and (b) reacting the compound with:

wherein X is a leaving group; wherein each of R^(4a) and R^(4b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; and wherein R^(4a) and R^(5a) are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl, therebyforming:

Also disclosed are methods for the treatment of a neurological and/orpsychiatric disorder associated with glutamate dysfunction in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for the treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal comprising the step of administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

The invention also relates to a product comprising a compound asdescribed herein and an additional pharmaceutical agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment or prevention of neurological and psychiatric disorders anddiseases.

In one aspect, the invention relates to a method for the treatment of adisorder of uncontrolled cellular proliferation in a mammal comprisingthe step of administering to the mammal a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method for thetreatment of a disorder of uncontrolled cellular proliferation in amammal comprising the step of administering to the mammal atherapeutically effective amount of at least one compound having astructure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

Additionally, the invention relates to a compound as defined herein foruse in the treatment or in the prevention of disorders of uncontrolledcellular proliferation.

Also disclosed are methods for potentiation of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for potentiation ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are methods for partial agonism of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for partial agonism ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are methods for enhancing cognition in a mammalcomprising the step of administering to the mammal an effective amountof at least one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for enhancingcognition in a mammal comprising the step of administering to the mammalan effective amount of at least one compound having a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are methods for modulating mGluR5 activity in a mammalcomprising the step of administering to the mammal an effective amountof at least one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for modulating mGluR5activity in a mammal comprising the step of administering to the mammalan effective amount of at least one compound having a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are methods for modulating mGluR5 activity in at leastone cell, comprising the step of contacting the at least one cell withan effective amount of at least one compound having a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, disclosed are methods for modulating mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with an effective amount of at least one compound havinga structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

Also disclosed are kits comprising at least one disclosed compound or atleast one disclosed product and one or more of at least one agent knownto increase mGluR5 activity; at least one agent known to decrease mGluR5activity; at least one agent known to treat a neurological and/orpsychiatric disorder; at least one agent known to treat a disease ofuncontrolled cellular proliferation; or instructions for treating adisorder associated with glutamate dysfunction.

Additionally, the invention relates to the use of a compound as definedherein in combination with an additional pharmaceutical agent for use inthe treatment or prevention of neurological and psychiatric disordersand diseases.

Also disclosed are methods for manufacturing a medicament comprisingcombining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent.Additionally, the invention relates to a compound as defined herein foruse as a medicament, and to a compound as defined herein for use in thetreatment or in the prevention of neurological and psychiatric disordersand diseases.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for the treatment of a disorderassociated with glutamate dysfunction in a mammal.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a schematic of the NMDA receptor.

FIG. 2 shows a schematic illustrating that activation of mGluR5potentiates NMDA receptor function.

FIG. 3 illustrates allosteric modulation of mGluR5.

FIG. 4 shows representative in vivo data for a compound of the presentinvention in the reversal of amphetamine-induced hyperlocomotion assay.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canrequire independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “orthosteric site” refers to the primarybinding site on a receptor that is recognized by the endogenous ligandor agonist for that receptor. For example, the orthosteric site in themGluR5 receptor is the site that glutamate binds.

As used herein, the term “mGluR5 receptor positive allosteric modulator”refers to any exogenously administered compound or agent that directlyor indirectly augments the activity of the mGluR5 receptor in thepresence or in the absence of glutamate in an animal, in particular amammal, for example a human. In one aspect, a mGluR5 receptor positiveallosteric modulator increases the activity of the mGluR5 receptor in acell in the presence of extracellular glutamate. The cell can be a humanembryonic kidney cell transfected with human mGluR5. The cell can be ahuman embryonic kidney cell transfected with rat mGluR5. The cell can bea human embryonic kidney cell transfected with a mammalian mGluR5. Theterm “mGluR5 receptor positive allosteric modulator” includes a compoundthat is a “mGluR5 receptor allosteric potentiator” or a “mGluR5 receptorallosteric agonist,” as well as a compound that has mixed activitycomprising pharmacology of both an “mGluR5 receptor allostericpotentiator” and an “mGluR5 receptor allosteric agonist.” The term“mGluR5 receptor positive allosteric modulator” also includes a compoundthat is a “mGluR5 receptor allosteric enhancer.”

As used herein, the term “mGluR5 receptor allosteric potentiator” refersto any exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand (suchas glutamate) when the endogenous ligand binds to the orthosteric siteof the mGluR5 receptor in an animal, in particular a mammal, for examplea human. The mGluR5 receptor allosteric potentiator binds to a siteother than the orthosteric site, that is, an allosteric site, andpositively augments the response of the receptor to an agonist or theendogenous ligand. While potentiators can induce desensitization of thecorresponding receptor, in certain aspects, allosteric potentiators donot induce desensitization of the receptor; thus, activity of a compoundas an mGluR5 receptor allosteric potentiator can provide advantages overthe use of a pure mGluR5 receptor allosteric agonist. Such advantagescan include, for example, increased safety margin, higher tolerability,diminished potential for abuse, and reduced toxicity.

As used herein, the term “mGluR5 receptor allosteric enhancer” refers toany exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand in ananimal, in particular a mammal, for example a human. In one aspect, theallosteric enhancer increases the affinity of the natural ligand oragonist for the orthosteric site. In another aspect, an allostericenhancer increases the agonist efficacy. The mGluR5 receptor allostericpotentiator binds to a site other than the orthosteric site, that is, anallosteric site, and positively augments the response of the receptor toan agonist or the endogenous ligand. An allosteric enhancer has noeffect on the receptor by itself and requires the presence of an agonistor the natural ligand to realize a receptor effect.

As used herein, the term “mGluR5 receptor allosteric agonist” refers toany exogenously administered compound or agent that directly augmentsthe activity of the mGluR5 receptor in the absence of the endogenousligand (such as glutamate) in an animal, in particular a mammal, forexample a human. The mGluR5 receptor allosteric agonist binds to a sitethat is distinct from the orthosteric glutamate site of the mGluR5receptor and influences the binding of an agonist or the natural ligandto the orthosteric site of the mGluR5 receptor. Because it does notrequire the presence of the endogenous ligand, activity of a compound asan mGluR5 receptor allosteric agonist provides advantages over the useof a pure mGluR5 receptor allosteric potentiator, such as more rapidonset of action.

As used herein, the term “mGluR5 receptor neutral allosteric ligand”refers to any exogenously administered compound or agent that binds toan allosteric site without affecting the binding or function of agonistsor the natural ligand at the orthosteric site in an animal, inparticular a mammal, for example a human. However, a neutral allostericligand can block the action of other allosteric modulators that act viathe same site.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more neurological and/or psychiatric disorder associated withglutamate dysfunction prior to the administering step. In some aspectsof the disclosed method, the subject has been diagnosed with a need forpositive allosteric modulation of metabotropic glutamate receptoractivity prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need for partialagonism of metabotropic glutamate receptor activity prior to theadministering step.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by modulation of mGluR5” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can modulatemGluR5. As a further example, “diagnosed with a need for modulation ofmGluR5” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by mGluR5 activity. Such a diagnosis can be in referenceto a disorder, such as a neurodegenerative disease, and the like, asdiscussed herein. For example, the term “diagnosed with a need forpositive allosteric modulation of metabotropic glutamate receptoractivity” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by positive allosteric modulation ofmetabotropic glutamate receptor activity. For example, “diagnosed with aneed for partial agonism of metabotropic glutamate receptor activity”means having been subjected to a physical examination by a person ofskill, for example, a physician, and found to have a condition that canbe diagnosed or treated by partial agonism of metabotropic glutamatereceptor activity. For example, “diagnosed with a need for treatment ofone or more neurological and/or psychiatric disorder associated withglutamate dysfunction” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave one or more neurological and/or psychiatric disorder associatedwith glutamate dysfunction.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mGluR5 activity) based upon an earlier diagnosis by a person of skilland thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target metabotropic glutamate receptor, or otherbiological entity together in such a manner that the compound can affectthe activity of the target (e.g., spliceosome, cell, etc.), eitherdirectly; i.e., by interacting with the target itself, or indirectly;i.e., by interacting with another molecule, co-factor, factor, orprotein on which the activity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response. In a yetfurther aspect, the response is in vitro. In a still further aspect, theresponse is in a human embryonic kidney cell transfected with humanmGluR5. In a yet further aspect, the response is a human embryonickidney cell transfected with rat mGluR5. In an even further aspect, therespons is in a human embryonic kidney cell transfected with a mammalianmGluR5.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance. In a yet further aspect, theinhibition is measured in vitro. In a still further aspect, theinhibition is measured in a human embryonic kidney cell transfected withhuman mGluR5. In a yet further aspect, the inhibition is measured in ahuman embryonic kidney cell transfected with rat mGluR5. In an evenfurther aspect, the inhibition is measured in a human embryonic kidneycell transfected with a mammalian mGluR5.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkylgroup can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiolas described herein. The term “biaryl” is a specific type of aryl groupand is included in the definition of “aryl.” Biaryl refers to two arylgroups that are bound together via a fused ring structure, as innaphthalene, or are attached via one or more carbon-carbon bonds, as inbiphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The term “halide,” “halo,” and “halogen,” can be used interchangeablyand as used herein refers to the halogens fluorine, chlorine, bromine,and iodine.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine,including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen; —(CH₂)₀₋₄R°;—(CH₂)₀₋₄OR°; —O(CH₂)₀₋₄R°, —O—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄CH(OR°)₂;—(CH₂)₀₋₄SR°; —(CH₂)₀₋₄Ph, which may be substituted with R°;—(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substituted with R°; —CH═CHPh, whichmay be substituted with R°; —(CH₂)₀₋₄O—(CH₂)₀₋₁-pyridyl which may besubstituted with R°; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R°)₂;—(CH₂)₀₋₄N(R°)C(O)R°; —N(R°)C(S)R°; —(CH₂)₀₋₄N(R°)C(O)NR°₂;—N(R°)C(S)NR°₂; —(CH₂)₀₋₄N(R°)C(O)OR°; —N(R°)N(R°)C(O)R°;—N(R°)N(R°)C(O)NR°₂; —N(R°)N(R°)C(O)OR°; —(CH₂)₀₋₄C(O)R°; —C(S)R°;—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄C(O)SR°; —(CH₂)₀₋₄C(O)OSiR°₃;—(CH₂)₀₋₄OC(O)R°; —OC(O)(CH₂)₀₋₄SR—, SC(S)SR°; —(CH₂)₀₋₄SC(O)R°;—(CH₂)₀₋₄C(O)NR°₂; —C(S)NR°₂; —C(S)SR°; —SC(S)SR°, —(CH₂)₀₋₄OC(O)NR°₂;—C(O)N(OR°)R°; —C(O)C(O)R°; —C(O)CH₂C(O)R°; —C(NOR°)R°; —(CH₂)₀₋₄SSR°;—(CH₂)₀₋₄S(O)₂R°; —(CH₂)₀₋₄S(O)₂OR°; —(CH₂)₀₋₄OS(O)₂R°; —S(O)₂NR°₂;—(CH₂)₀₋₄S(O)R°; —N(R°)S(O)₂NR°₂; —N(R°)S(O)₂R°; —N(OR°)R°; —C(NH)NR°₂;—P(O)₂R°; —P(O)R°₂; —OP(O)R°₂; —OP(O)(OR°)₂; SiR°₃; —(C₁₋₄ straight orbranched alkylene)O—N(R°)₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R°)₂, wherein each R° may be substituted as definedbelow and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(°), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking twoindependent occurrences of R° together with their intervening atoms),are independently halogen, —(CH₂)₀₋₂R, -(haloR^()), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN, —N₃,—(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(),—(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(),—(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, —OSiR^() ₃, —C(O)SR^(), —(C₁₋₄straight or branched alkylene)C(O)OR^(), or —SSR^() wherein each R^()is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R° include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, brosylate, and halides.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitatation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel lines(bonds to atoms below the plane). The Cahn-Inglod-Prelog system can beused to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labelled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. Unless stated to the contrary, theinvention includes all such possible tautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

The following abbreviations are used herein. AcOEt: ethyl acetate. BuOH:1-Butanol. DMAP: 4-Dimethylaminopyridine. DCM: Dichloromethane. DIPE:diisopropylether. DIPEA: N,N-diisopropylethylamine. DMF: dimethylformamide. DMSO: dimethylsulfoxide. EDC:1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride. EtOH:ethanol. HPLC: high-performance liquid chromatography. HOBt:1-hydroxybenzotriazole. iPrOH: 2-Propanol. LCMS: liquidchromatography/mass spectrometry. [M+H]+: protonated mass of the freebase of the compound. M.p.: melting point. MeCN: Acetonitrile. MeOH:methanol. Min: Minutes. NMR: nuclear magnetic resonance. Rt: retentiontime (in minutes). THF: tetrahydrofuran.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Compounds

In one aspect, the invention relates to compounds useful as positiveallosteric modulators of the metabotropic glutamate receptor subtype 5(mGluR5). More specifically, in one aspect, the present inventionrelates to compounds that allosterically modulate mGluR5 receptoractivity, affecting the sensitivity of mGluR5 receptors to agonistswithout acting as orthosteric agonists themselves. The compounds can, inone aspect, exhibit subtype selectivity.

In one aspect, the disclosed compounds exhibit positive allostericmodulation of mGluR5 response to glutamate as an increase in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In furtheraspect, the human embryonic kidney cells are transfected with humanmGluR5. In yet a further aspect, human embryonic kidney cells aretransfected with mGluR5 of a mammal.

In one aspect, the compounds of the invention are useful in thetreatment of neurological and psychiatric disorders associated withglutamate dysfunction and other diseases in which metabotropic glutamatereceptors are involved, as further described herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, the invention relates to a compound having a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

In various aspects, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, wherein thecompound exhibits potentiation of mGluR5 response to glutamate as anincrease in response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a still further aspect, wherein Ar¹ is phenyl. In a yetfurther aspect, wherein Ar¹ is phenyl with 1-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl. In an even further aspect, wherein Ar¹ ispyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In further aspect,wherein Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl. In an even further aspect, wherein Ar¹ is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a yet further aspect,wherein Ar² is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a yet further aspect, Ar¹ is phenyl and Ar² is phenylsubstituted with 0-3 substituents selected from —F, —Cl, —Br, and —I.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar² is phenyl. In a yet further aspect, wherein Ar² is phenylwith 1-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a stillfurther aspect, wherein Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In an even further aspect, Ar² is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl. In a further aspect, wherein Ar²is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has1-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl. In a yet further aspect, wherein Ar¹ isphenyl; and wherein Ar² is phenyl with 0-3 substituents selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, andpolyhalo C1-C4 alkyl. In a still further aspect, wherein Ar¹ is phenyl;and wherein Ar² is phenyl with 1-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In an even further aspect, wherein Ar¹ is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; and wherein Ar² isphenyl. In a further aspect, wherein Ar¹ is phenyl with 1-3 substituentsselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl; and wherein Ar² is phenyl.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl with 1-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; and wherein Ar² is phenyl with 1-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl. In a still further aspect, wherein Ar¹ isphenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; andwherein Ar² is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl and has 0-3 substituents selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.In a yet further aspect, wherein Ar¹ is phenyl; and wherein Ar² ispyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In an even furtheraspect, wherein Ar¹ is phenyl with 1-3 substituents selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, andpolyhalo C1-C4 alkyl; and wherein Ar² is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl. In a further aspect, wherein Ar¹ is phenyl;and wherein Ar² is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl. In a yet further aspect, wherein Ar¹ is phenyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; and wherein Ar² ispyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl. In a stillfurther aspect, wherein Ar¹ is phenyl; and wherein Ar² is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In an even furtheraspect, wherein Ar¹ is phenyl with 1-3 substituents selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, andpolyhalo C1-C4 alkyl; and wherein Ar² is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl and has 1-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl.

In a further aspect, the compound has a structure represented by aformula:

In various aspects, as described above, the disclosed compounds bearsubstituents, as shown in the formula below:

Suitable substituents are described below.

a. Ar¹ Groups

In one aspect, Ar¹ is phenyl with 0-3 substituents selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, andpolyhalo C1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a further aspect, Ar¹ is unsubstituted. In a yet furtheraspect, Ar¹ has 1, 2, or 3 substituents.

In one aspect, Ar¹ is phenyl. In one aspect, Ar¹ is phenyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.

In one aspect, Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl. In a yet further aspect, Ar¹ is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl and has 1-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl.

In one aspect, Ar¹ is substituted with 1-3 groups selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a further aspect, Ar¹ is substituted with 1-3 halogens.In a yet further aspect, Ar¹ is substituted with 1-3 groups selectedfrom halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy. In a still furtheraspect, Ar¹ is substituted with 1-3 groups selected from halogen,methyl, trifluoromethyl, ethyl, propyl, and butyl. In a further aspect,halogen is fluoro, chloro, or bromo. In a still further aspect, halogenis fluoro.

In one aspect, Ar¹ is substituted with 1-3 groups selected from methoxy,trifluoromethoxy, ethoxy, propyloxy, or butyloxy.

b. Ar² Groups

In one aspect, Ar² is phenyl with 0-3 substituents selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, andpolyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a further aspect, Ar² is unsubstituted. In a yet furtheraspect, Ar² has 1, 2, or 3 substituents.

In one aspect, Ar² is phenyl. In a further aspect, Ar² is phenyl with1-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.

In one aspect, Ar² is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl. In a further aspect, Ar² is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl and has 1-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl.

In one aspect, Ar² is substituted with 1-3 groups selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a further aspect, Ar² is substituted with 1-3 halogens.In a yet further aspect, Ar² is substituted with 1-3 groups selectedfrom halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy. In a still furtheraspect, Ar² is substituted with 1-3 groups selected from halogen,methyl, trifluoromethyl, ethyl, propyl, or butyl. In a further aspect,halogen is fluoro, chloro, or bromo. In a still further aspect, halogenis fluoro.

In one aspect, Ar² is substituted with 1-3 groups selected from methoxy,trifluoromethoxy, ethoxy, propyloxy, or butyloxy.

c. R^(1a) Groups

In one aspect, R^(1a) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(1a) isselected from hydrogen and C1-C4 alkyl. In a further aspect, R^(1a) ishydrogen. In a further aspect, R^(1a), R^(1b), and R² are each hydrogen.In a still further aspect, R^(1a), R^(1b), R², R^(3a), and R^(3b) areeach hydrogen.

d. R^(1b) Groups

In one aspect, R^(1b) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(1b) isselected from hydrogen and C1-C4 alkyl. In a further aspect, R^(1b) ishydrogen.

e. R² Groups

In one aspect, R² is selected from hydrogen, halogen, cyano, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a furtheraspect, R² is selected from hydrogen and C1-C4 alkyl. In a furtheraspect, R² is hydrogen. In an even further aspect, R² is selected fromhalogen, cyano, and C1-C4 alkyl. In a further aspect, R² is selectedfrom hydrogen and C1-C4 alkyl. In a still further aspect, R² is selectedfrom halogen, methyl, trifluoromethyl, ethyl, propyl, and butyl.

In various further aspects, R² is selected from hydrogen, halogen,cyano, —NH₂, C1-C4 alkyl, monohalo C1-C4 alkyl, C1-C4 alkoxy, andpolyhalo C1-C4 alkyl.

f. R^(3a) Groups

In one aspect, each of R^(3a) and R^(3b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl,or are covalently bonded and, together with the intermediate carbon,comprise an optionally substituted 3- to 7-membered spirocycloalkyl. Inone aspect, R^(3a) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(3a) isselected from hydrogen and C1-C4 alkyl. In a further aspect, R^(3a) ishydrogen. In a yet further aspect, R^(3a) and R^(3b) are both hydrogen.In a still further aspect, R^(1a), R^(1b), R², R^(3a), and R^(3b) areeach hydrogen. In a further aspect, R^(3a) is hydrogen. In a stillfurther aspect, R^(3a) is C1-C4 alkyl. In a yet further aspect, R^(3a)is selected from methyl, trifluoromethyl, ethyl, propyl, and butyl.

In one aspect, each of R^(3a) and R^(3b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.

In one aspect, R^(3a) and R^(3b) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a further aspect, R^(3a) and R^(3b) are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl.

g. R^(3b) Groups

In one aspect, R^(3b) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(3b) isselected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl. In a further aspect, R^(3b) is selected from hydrogen andC1-C4 alkyl. In a further aspect, R^(3b) is hydrogen. In a furtheraspect, each of R^(3a) and R^(3b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.In a still further aspect, R^(3b) is C1-C4 alkyl. In a yet furtheraspect, wherein R^(3b) is selected from methyl, trifluoromethyl, ethyl,propyl, and butyl.

In one aspect, R^(3a) and R^(3b) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a further aspect, R^(3a) and R^(3b) are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl.

h. R^(4a) Groups

In one aspect, each of R^(4a) and R^(4b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl,or are covalently bonded and, together with the intermediate carbon,comprise an optionally substituted 3- to 7-membered spirocycloalkyl. Ina further aspect, R^(4a) is selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect,R^(4a) is selected from hydrogen and C1-C4 alkyl. In a further aspect,R^(4a) is hydrogen.

In a further aspect, each of R^(4a) and R^(4b) is independently selectedfrom hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl. In a yet further aspect, R^(4a) and R^(4b) are both hydrogen. Inan even further aspect, R^(4a) is C1-C4 alkyl. In a further aspect,R^(4a) is selected from methyl, trifluoromethyl, ethyl, propyl, andbutyl. In further aspect, R^(4a) is methyl. In an even further aspect,R^(4a) and R^(5a) are each methyl.

In one aspect, R^(4a) and R^(5a) are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl.

In one aspect, R^(4a) and R^(5a) are not directly covalently bonded.

In one aspect, R^(4a) and R^(5a) are directly covalently bonded tocomprise, together with the intermediate atoms, a 3-, 4-, 5-, 6-, or7-membered fused cycloalkyl. In a further aspect, R^(4a) and R^(5a) aredirectly covalently bonded to comprise, together with the intermediateatoms, a substituted 3-, 4-, 5-, 6-, or 7-membered fused cycloalkyl. Ina yet further aspect, the fused cycloalkyl is substituted with 1 or 2groups selected from methyl, ethyl, and propyl.

i. R^(4b) Groups

In one aspect, R^(4b) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(4b) isselected from hydrogen and C1-C4 alkyl. In a still further aspect,R^(4b) is hydrogen. In an even further aspect, R^(4b) is C1-C4 alkyl. Ina further aspect, R^(4b) is selected from methyl, trifluoromethyl,ethyl, propyl, and butyl.

In one aspect, R^(4a) and R^(4b) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a further aspect, R^(4a) and R^(4b) are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl.

j. R^(5a) Groups

In one aspect, each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl,or are covalently bonded and, together with the intermediate carbon,comprise an optionally substituted 3- to 7-membered spirocycloalkyl. Ina further aspect, R^(5a) is selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect,R^(5a) is selected from hydrogen and C1-C4 alkyl. In a further aspect,R^(5a) is hydrogen.

In a further aspect, R^(5a) is selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a still furtheraspect, R^(5a) and R^(5b) are both hydrogen. In a still further aspect,R^(5a) is C1-C4 alkyl. In a further aspect, R^(5a) is selected frommethyl, trifluoromethyl, ethyl, propyl, and butyl. In an even furtheraspect, R^(4a) and R^(5a) are each methyl.

In one aspect, R^(4a) and R^(5a) are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl.

In one aspect, R^(5a) and R^(5b) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a further aspect, R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl.

In one aspect, R^(4a) and R^(5a) are not directly covalently bonded.

In one aspect, R^(4a) and R^(5a) are directly covalently bonded tocomprise, together with the intermediate atoms, a 3-, 4-, 5-, 6-, or7-membered fused cycloalkyl. In a further aspect, R^(4a) and R^(5a) aredirectly covalently bonded to comprise, together with the intermediateatoms, a substituted 3-, 4-, 5-, 6-, or 7-membered fused cycloalkyl. Ina yet further aspect, the fused cycloalkyl is substituted with 1 or 2groups selected from methyl, ethyl, and propyl.

k. R^(5b) Groups

In one aspect, R^(5b) is selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl. In a further aspect, R^(5b) isselected from hydrogen and C1-C4 alkyl. In a further aspect, R^(5b) ishydrogen. In a further aspect, R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.In a further aspect, R^(5b) is hydrogen. In a yet further aspect, R^(5b)is C1-C4 alkyl. In a further aspect, R^(5b) is selected from methyl,trifluoromethyl, ethyl, propyl, and butyl.

In one aspect, R^(5a) and R^(5b) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a further aspect, R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl.

It is contemplated that the disclosed compounds can be used inconnection with the disclosed methods, compositions, products, uses, andkits.

2. Example Compounds

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as a racemate orstereochemically pure enantiomer selected from:

In yet a further aspect, the compound produced exhibits positiveallosteric modulation of mGluR5 response to glutamate as an increase inresponse to non-maximal concentrations of glutamate in human embryonickidney cells transfected with rat mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound. In a further aspect, human embryonic kidney cells aretransfected with human mGluR5. In yet a further aspect, human embryonickidney cells are transfected with mammalian mGluR5. In yet a furtheraspect, the compound produced exhibits positive allosteric modulation ofmGluR5 after contacting a cell expressing mGluR5.

In a further aspect, the disclosed compounds are allosteric modulatorsof mGluR5, in particular, positive allosteric modulators of mGluR5. Thedisclosed compounds can potentiate glutamate responses by binding to anallosteric site other than the glutamate orthosteric binding site. Theresponse of mGluR5 to a concentration of glutamate is increased when thedisclosed compounds are present. In a further aspect, the disclosedcompounds can have their effect substantially at mGluR5 by virtue oftheir ability to enhance the function of the receptor.

It is contemplated that one or more compounds can optionally be omittedfrom the disclosed invention.

3. Positive Allosteric Modulation of mGluR5 Response

Generally, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. For example, acompound can exhibit positive allosteric modulation of mGluR5 (e.g.,rmGluR5) with an EC₅₀ of less than about 10,000 nM, of less than about5,000 nM, of less than about 1,000 nM, of less than about 500 nM, or ofless than about 100 nM. Alternatively, the disclosed compounds exhibitpotentiation of mGluR5 response to glutamate as an increase in responseto non-maximal concentrations of glutamate in human embryonic kidneycells transfected with human mGluR5 (H10H cell line) in the presence ofthe compound, compared to the response to glutamate in the absence ofthe compound. For example, a compound can exhibit positive allostericmodulation of mGluR5 (e.g., hmGluR5) with an EC₅₀ of less than about10,000 nM, of less than about 5,000 nM, of less than about 1,000 nM, ofless than about 500 nM, or of less than about 100 nM.

C. Metabotropic Glutamate Receptor Activity

The utility of the compounds in accordance with the present invention aspotentiators of metabotropic glutamate receptor activity, in particularmGluR5 activity, can be demonstrated by methodology known in the art.Human embryonic kidney (HEK) cells transfected with rat mGluR5 wereplated in clear bottom assay plates for assay in a Functional DrugScreening System (FDSS). In the alternative assay, HEK cells transfectedwith human mGluR5 (H10H cell line) were plated for assay in the FDSS.Rat assay results were found to correlate well with human assay results.The cells were loaded with a Ca²⁺-sensitive fluorescent dye (e.g.,Fluo-4), and the plates were washed and placed in the FDSS instrument.After establishment of a fluorescence baseline for twelve seconds, thecompounds of the present invention were added to the cells, and theresponse in cells was measured. Alternatively, in various furtheraspects, after establishment of a fluorescence baseline for about threeseconds, the compounds of the present invention were added to the cells,and the response in cells was measured. Five minutes later, an mGluR5agonist (e.g., glutamate, 3,5-dihydroxyphenylglycine, or quisqualate)was added to the cells, and the response of the cells was measured.Potentiation of the agonist response of mGluR5 by the compounds in thepresent invention was observed as an increase in response to non-maximalconcentrations of agonist (here, glutamate) in the presence of compoundcompared to the response to agonist in the absence of compound.

The above described assay operated in two modes. In the first mode, arange of concentrations of the present compounds were added to cells,followed by a single fixed concentration of agonist. If a compound actedas a potentiator, an EC₅₀ value for potentiation and a maximum extent ofpotentiation by the compound at this concentration of agonist wasdetermined by non-linear curve fitting. In the second mode, severalfixed concentrations of the present compounds were added to variouswells on a plate, followed by a range of concentrations of agonist foreach concentration of present compound; the EC₅₀ values for the agonistat each concentration of compound were determined by non-linear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5potentiation at a given concentration of the present compound. Anincrease in the EC₅₀ value of the agonist with increasing concentrationsof the present compounds (a rightward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5antagonism at a given concentration of the present compound. The secondmode also indicates whether the present compounds also affect themaximum response to mGluR5 to agonists.

In one aspect, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith a mammalian mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. For example, humanembryonic kidney cells can be transfected with human mGluR5. Forexample, human embryonic kidney cells can be transfected with ratmGluR5. For example, a compound can exhibit positive allostericmodulation of mGluR5 (e.g., rmGluR5) with an EC₅₀ of less than about10,000 nM, of less than about 5,000 nM, of less than about 1,000 nM, ofless than about 500 nM, or of less than about 100 nM. Alternatively, thedisclosed compounds exhibit potentiation of mGluR5 response to glutamateas an increase in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human mGluR5 (H10H cellline) in the presence of the compound, compared to the response toglutamate in the absence of the compound. For example, a compound canexhibit positive allosteric modulation of mGluR5 (e.g., hmGluR5) with anEC₅₀ of less than about 10,000 nM, of less than about 5,000 nM, of lessthan about 1,000 nM, of less than about 500 nM, or of less than about100 nM.

In particular, the disclosed compounds exhibit activity in potentiatingthe mGluR5 receptor in the aforementioned assays, generally with an EC₅₀for potentiation of less than about 10 μM. Preferred compounds withinthe present invention had activity in potentiating the mGluR5 receptorwith an EC₅₀ for potentiation of less than about 500 nM. Preferredcompounds further caused a leftward shift of the agonist EC₅₀ by greaterthan 3-fold. These compounds did not cause mGluR5 to respond in theabsence of agonist, and they did not elicit a significant increase inthe maximal response of mGluR5 to agonists. These compounds are positiveallosteric modulators (potentiators) of human and rat mGluR5 and wereselective for mGluR5 compared to the other seven subtypes ofmetabotropic glutamate receptors.

In vivo efficacy for disclosed compounds can be measured in a number ofpreclinical rat behavioral model where known, clinically usefulantipsychotics display similar positive responses. For example,disclosed compounds can reverse amphetamine-induced hyperlocomotion inmale Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg p.o.

D. Methods of Making the Compounds

In one aspect, the invention relates to methods of making compoundsuseful as positive allosteric modulators of the metabotropic glutamatereceptor subtype 5 (mGluR5), which can be useful in the treatmentneurological and psychiatric disorders associated with glutamatedysfunction and other diseases in which metabotropic glutamate receptorsare involved.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, inaddition to other standard manipulations known in the literature or toone skilled in the art. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

In a further aspect, a compound comprises the product of the disclosedmethods. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

In one aspect, the invention relates to a synthetic method comprisingthe steps of: (a) providing a compound having a structure represented bya formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; and wherein R^(4a) andR^(5a) are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkyl, and (b) reacting the compound with Ar²COX or Ar²CO₂H,wherein X is a leaving group, and wherein Ar² is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar² is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, thereby forming anamide. In a further aspect, the leaving group is halogen.

In a yet further aspect, the amide formed has a structure represented bya formula:

In one aspect, the invention relates to a synthetic method comprisingthe steps of: (a) providing a compound having a structure represented bya formula:

wherein R is hydrogen or alkyl; wherein Ar¹ is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar¹ is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(1a)and R^(1b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; and wherein R² isselected from hydrogen, halogen, cyano, C1-C4 alkyl, monohalo C1-C4alkyl, and polyhalo C1-C4 alkyl, and (b) reacting the compound with:

wherein X is a leaving group; wherein each of R^(4a) and R^(4b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; and wherein R^(4a) and R^(5a) are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl, therebyforming:

In a further aspect, the leaving group is halogen. In a yet furtheraspect, the providing step comprises reacting hydrazine with a compoundhaving a structure represented by a formula:

In a further aspect, the synthetic method further comprises the steps ofdeprotecting the amine and cyclizing to form a compound having astructure represented by a formula:

In a further aspect, the synthetic method further comprises the step ofreducting the compound formed above to form a compound having astructure represented by a formula:

In a further aspect, the synthetic method further comprises the step ofreacting the product produced above with Ar²COX or Ar²CO₂H, wherein X isa leaving group, and wherein Ar² is phenyl with 0-3 substituentsselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, thereby forming an amide. In a yet furtheraspect, the amide formed has a structure represented by a formula:

In one aspect, the invention relates to a synthetic method comprisingthe steps of: (a) providing a compound having a structure represented bya formula:

wherein each R is independently hydrogen or alkyl; and wherein R² isselected from hydrogen, halogen, cyano, C1-C4 alkyl, monohalo C1-C4alkyl, and polyhalo C1-C4 alkyl, and, (b) reacting the compound with:

wherein X is a leaving group; wherein each of R^(4a) and R^(4b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or are covalently bonded and, together withthe intermediate carbon, comprise an optionally substituted 3- to7-membered spirocycloalkyl; and wherein R^(4a) and R^(5a) are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl, therebyforming:

In a further aspect, the leaving group is halogen. In a yet furtheraspect, the synthetic method further comprises the steps of deprotectingthe amine and cyclizing to form a compound having a structurerepresented by a formula:

In a further aspect, the synthetic method further comprises the steps ofalkylation and reduction of the above product to form a compound havinga structure represented by a formula:

In a further aspect, the synthetic method further comprises the step ofperforming a Mitsunobu reaction with Ar¹OH on the above product, therebyproviding a compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl.

In a further aspect, the synthetic method further comprises the steps ofdeprotecting the amine formed above and reacting with Ar²COX or Ar²CO₂H,wherein X is a leaving group, and wherein Ar² is phenyl with 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar² is pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, thereby forming anamide. In a still further aspect, the amide formed has a structurerepresented by a formula:

In one aspect, the disclosed compounds comprise the products of thesynthetic methods described herein. In a further aspect, the disclosedcompounds comprise a compound produced a synthetic method describedherein.

In a further aspect, the compound produced exhibits potentiation ofmGluR5 response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith mGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundproduced by one the synthetic methods described herein and apharmaceutically acceptable carrier.

1. Reaction Scheme I

In one aspect, bicyclic pyrazole analogs can be prepared as shown below.Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein.

Examples of bicycle pyrazoles of type 1.2 can be prepared starting withthe pyrazole of type 1.1 as outlined in Scheme Ia. Briefly, a compoundrepresented by formula 1.1 in Scheme Ia is reacted with an acid halidederivative, wherein X represents a halogen atom, in the presence of abase. In one aspect, the halogen is chlorine. Appropriate bases for thereaction described in Scheme Ia can be pyridine ordiisopropylethylamine. Solvents suitable for this reaction can be aninert solvent, including dichloromethane. In one aspect, the reaction iscarried out at a temperature of about −10° C. to 25° C. for a period oftime to ensure the completion of the reaction.

Alternatively, examples of bicycle pyrazoles of type 1.2 can be preparedstarting with the pyrazole of type 1.1 as outlined in Scheme Ib.Briefly, a compound represented by formula 1.1 in Scheme Ib is reactedwith a carboxylic acid in the presence of a coupling reagent and a base.In one aspect, the coupling reagent can be2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and the base can beN,N-diisopropylethylamine. Solvents suitable for this reaction can beN,N-dimethylformamide. In a further aspect, the reaction is carried outat a temperature of about 0° C. to 40° C. for a period of time to ensurethe completion of the reaction.

2. Reaction Scheme II

Alternatively, one can prepare the pyrazole intermediate (compound type1.1 in Scheme Ia or Scheme Ib) by reaction shown in Scheme II below. Forexample, a compound represented by compound 2.6 can be reacted with anappropriate reducing reagent in an inert solvent. In one aspect, thereducing agent can be lithium aluminum hydride and the inert solvent canbe tetrahydrofuran. The reaction is carried out at a temperature ofabout −10° C. to 25° C. for a period of time to ensure the completion ofthe reaction. The reaction scheme shown below in Scheme II outlines asynthetic method to prepare suitable compounds of the type representedby compound 2.6.

Briefly an aromatic ether (see the compound represented by structure2.2) is reacted with a diester (compound 2.1) in the presence of a baseat a temperature of about 0° C. and 40° C. for a period of time thatallows the completion of the reaction. In one aspect, the diester isdiethyl oxalate, the aromatic ether is a 1-aryloxypropan-2-one, and thebase is sodium ethoxide. In a further aspect, the reaction is carriedout in an inert solvent. In a yet further aspect, the inert solvent isethanol. Suitable diesters (compound 2.1) and aryl ethers (compound 2.2)are commercially available.

The product of the above reaction, compound 2.3, is reacted withhydrazine in an inert solvent at a temperature of about 70° C. and 110°C. for a period of time that allows the completion of the reaction toyield compound 2.4. Similar synthetic methods are described in US2005143443 A1 20050630. In one aspect, the inert solvent is ethanol.Alternatively, compounds represented by compound 2.4 can be obtainedcommercially.

Reaction of compound 2.4 with an appropriate alcohol (as shown in SchemeII wherein X is OH) in a Mitsunobu type reaction in the presence of atriarylphosphine and a dialkyl azodicarboxylate reagent in an inertsolvent can be used to prepare compounds represented by compound 2.5. Inone aspect, the triarylphosphine is triphenylphosphine, the dialkylazodicarboxylate reagent is di-tert-butyl azodicarboxylate (DTBAD), andthe inert solvent is tetrahydrofuran. In a further aspect, the reactionis carried by heating either conventionally or under microwaveirradiation for a period of time to ensure the completion of thereaction. Alternatively, compound 2.4 can be reacted with an appropriatealkylating reagent (as shown in Scheme II wherein X represents a leavinggroup) in the presence of base in an inert solvent at a temperature ofabout 0° C. to 40° C. for a period of time to ensure the completion ofthe reaction. In one aspect, the base is cesium carbonate and the inertsolvent is N,N-dimethylformamide. In a further aspect, the leavinggroup, X, is Br.

Compound 2.6 can be synthesized by reaction of compound 2.5 with asuitable acid in an inert solvent at a temperature of about 0° C. and40° C. for a period of time to ensure the completion of the reaction,followed by treatment with a base at a temperature of about 0° C. and40° C. for a period of time to ensure the completion of the reaction. Inone aspect, the acid is hydrochloric acid, the inert solvent is1,4-dioxane, and the base is sodium carbonate.

3. Reaction Scheme III

Alternatively, one can prepare a pyrazole intermediate (compound 3.7 inScheme III) as shown in Scheme III below. The product of the reactionscheme III, that is a compound represented by compound 3.7, can be usedin the preparation of bicyclic pyrazoles using methods described abovein Reaction Scheme I.

A compound represented by compound 3.2 can be prepared by reaction of acompound represented by compound 3.1 with an alkylating reagent in thepresence of a base in an inert solvent a temperature of about between 0°C. and 40° C., for a period of time to ensure the completion of thereaction. In one aspect, the alkylating agent is2-(2-tert-butoxycarbonylamino)ethylbromide, the base is cesiumcarbonate, and the inert solvent is N,N-dimethylformamide.

A compound represented by compound 3.3 can be prepared by reacting acompound represented by compound 3.2 in the presence of an acid in aninert solvent at a temperature of about 0° C. to 40° C. for a period oftime to ensure the completion of the reaction followed by treatment witha base at a temperature of about 0° C. to 40° C., for a period of timeto ensure the completion of the reaction. In one aspect, the acid ishydrochloric acid, the base is sodium carbonate, and the inert solventis 1,4-dioxane.

A compound represented by compound 3.4 can be prepared by reacting acompound represented by compound 3.3 with an alkylating reagent in thepresence of a base in a suitable inert solvent at a temperature of about0° C. to 40° C. for a period of time to ensure the completion of thereaction. In one aspect, the alkylating agent is benzylbromide, the baseis sodium hydride, and the inert solvent is N,N-dimethylformamide.

A compound represented by compound 3.5 can be prepared by reacting acompound represented by compound 3.4 with a suitable reducing reagent ina suitable inert solvent at a temperature of about 10° C. and 25° C. fora period of time to ensure the completion of the reaction. In oneaspect, the reducing agent is lithium aluminum hydride and the inertsolvent is tetrahydrofuran.

A compound represented by compound 3.6 can be prepared by aMitsunobu-type reaction between a compound represented by compound 3.5and an aryl alcohol in the presence of a triarylphosphine and a dialkylazodicarboxylate reagent in an inert solvent. In one aspect, thetriarylphosphine is triphenylphosphine, the dialkyl azodicarboxylatereagent is di-tert-butyl azodicarboxylate (DTBAD), and the inert solventis tetrahydrofuran. In a further aspect, the reaction is heated byconventional means or under microwave irradiation. Appropriate arylalcohols for preparation of the desired pyrazole intermediates can becommercially obtained.

A compound represented by compound 3.7 can be prepared by reacting acompound represented by compound 3.6 with ammonium formate in thepresence of a suitable catalyst at a reaction temperature of about 70°C. to 110° C. for a period of time that allows the completion of thereaction. In one aspect, the catalyst is 10% palladium on charcoal.

4. Reaction Scheme IV

In one aspect, bicyclic pyrazole analogs such as compound 4.7 (shown inScheme IV below) can be prepared as shown below. The product of thereaction scheme IV, that is a compound represented by compound 4.7, canbe used in the preparation of bicyclic pyrazoles using methods describedabove in Reaction Scheme I.

A compound represented by compound 4.1 can be prepared by reaction of acompound represented by compound 2.4 with a protecting group such asdimethylsulfamoyl chloride in an inert solvent at a temperature of about0° C. to 40° C. for a period of time to ensure the completion of thereaction.

A compound represented by compound 4.2 can be prepared by reaction of acompound represented by compound 4.1 with an amine and a Grignardreagent at low temperature to prepare the Weinreb amide hydrochloridefor a period of time to ensure the completion of the reaction. In oneaspect, the amine is N,O-dimethylhydroxylamine. In a further aspect, theGrignard reagent is isopropylmagnesium chloride. In an even furtheraspect, the temperature is about −70° C. to −80° C.

A compound represented by compound 4.3 can be prepared by reaction of acompound represented by compound 4.2 with a Grignard reagent at lowtemperature for a period of time to ensure the completion of thereaction. In one aspect, the Grignard reagent is methylmagnesiumbromide. In a further aspect, the temperature is about −70° C. to −80°C.

A compound represented by compound 4.4 can be prepared by reaction of acompound represented by compound 4.3 with an acid in an inert solvent ata convenient temperature for a period of time to ensure the completionof the reaction. In one aspect, the acid is hydrochloric acid. In afurther aspect, the inert solvent is methanol. In a yet further aspect,the temperature is about 45° C. to 85° C.

A compound represented by compound 4.5 can be prepared by reaction of acompound represented by compound 4.4 with an alkylating reagent, whereinX represents a leaving group, in the presence of a base in an inertsolvent at a convenient temperature for a period of time to ensure thecompletion of the reaction. In one aspect, the leaving group X is Br. Ina further aspect, the base is potassium carbonate. In a yet furtheraspect, the inert solvent is N,N-dimethylformamide. In a still furtheraspect, the temperature is about between 0° C. to 40° C.

A compound represented by compound 4.6 can be prepared by reaction of acompound represented by compound 4.5 with an acid in an inert solvent ata convenient temperature for a period of time to ensure the completionof the reaction. In one aspect, the acid is hydrochloric acid. In afurther aspect, the inert solvent is 1,4-dioxane. In a yet furtheraspect, the temperature is about 0° C. to 40° C.

A compound represented by compound 4.7 can be prepared by reaction of acompound represented by compound 4.6 with a reducing agent in an inertsolvent at a convenient temperature for a period of time to ensure thecompletion of the reaction. In one aspect, the reducing agent is sodiumtriacetoxyborohydride. In a further aspect, the inert solvent isdichloromethane. In a still further aspect, the temperature is about−10° C. to 25° C.

5. Reaction Scheme V

Alternatively, bicyclic pyrazole analogues such as compound 4.7 (shownin Scheme V below) can be prepared as shown below. The product of thereaction scheme V, that is a compound represented by compound 4.7, canbe used in the preparation of bicyclic pyrazoles using methods describedabove in Reaction Scheme I.

A compound represented by compound 5.1 can be prepared by reacting acompound represented by compound 2.5 with a suitable reducing reagent ina suitable inert solvent at a temperature of about −10° C. and 25° C.for a period of time to ensure the completion of the reaction. In oneaspect, the reducing agent is lithium aluminum hydride and the inertsolvent is tetrahydrofuran.

A compound represented by compound 5.2 can be prepared by reacting acompound represented by compound 5.1 with a suitable oxidizing reagentin a suitable inert solvent at a temperature of about 80° C. and 120° C.for a period of time to ensure the completion of the reaction. In oneaspect, the oxidizing agent is manganese dioxide and the inert solventis 1,4-dioxane.

A compound represented by compound 5.3 can be prepared by reaction of acompound represented by compound 5.2 with an acid in an inert solvent ata convenient temperature for a period of time to ensure the completionof the reaction. In one aspect, the acid is hydrochloric acid. In afurther aspect, the inert solvent is 1,4-dioxane. In a yet furtheraspect, the temperature is about 0° C. to 40° C.

A compound represented by compound 4.7 can be prepared by reaction of acompound represented by compound 5.3 with Ruppert's reagent in acidicconditions in an inert solvent at a convenient temperature for a periodof time to ensure the completion of the reaction. In one aspect, theacid is hydrofluoric acid genearated, in situ, from potassium hydrogenfluoride and trifluoroacetic acid. In a further aspect, the inertsolvent is a mixture of acetonitrile and N,N-dimethylformamide. In astill further aspect, the temperature is about −10° C. to 25° C.

6. Reaction Scheme VI

Alternatively, one can prepare the bicyclic pyrazole analogues of type1.2 by reaction shown in Scheme VI below. For example, a compoundrepresented by compound 6.1 can be reacted with an appropriatehalogenating reagent in an inert solvent. In one aspect, thehalogenating agent can be N-chlorosuccinimide and the inert solvent canbe chloroform. In a further aspect, the halogenating reagent can beN-fluoro-N-(chloromethyl)triethylenediamine bis(tetrafluoroborate) andthe inert solvent can be acetonitrile. The reactions are carried out ata temperature of about 60° C. to 100° C. for a period of time to ensurethe completion of the reaction. Compound 6.1 can be synthesizedfollowing the reaction conditions shown above in Scheme I.

7. Reaction Scheme VII

Alternatively, one can prepare the bicyclic pyrazole analogues of type1.2 by reaction shown in Scheme VII below. For example, a compoundrepresented by compound 7.1 can be reacted with a suitable boronic acidin the presence of an appropriate catalyst and a base in an inertsolvent. In one aspect, the boronic acid can be methylboronic acid, thecatalyst can be tetrakis(triphenylphosphine)palladium(0), the base issodium carbonate and the inert solvent can be 1,4-dioxane. The reactionis carried out at a temperature of about 80° C. to 120° C. for a periodof time to ensure the completion of the reaction. Compound 7.1 can besynthesized following the reaction conditions shown above in Scheme VI.

8. Reaction Scheme VIII

Alternatively, one can prepare the bicyclic pyrazole analogues of type1.2 by reaction shown in Scheme VIII below. For example, a compoundrepresented by compound 7.1 can be reacted with an appropriate amine inthe presence of a suitable catalyst and an appropriate ligand and a basein an inert solvent, followed by treatment with an acid. In one aspect,the amine can be benzophenone imine, the catalyst istris(dibenzylideneacetone) dipalladium(0), the ligand can berac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, the base is sodiumtert-butoxide and the inert solvent can be toluene. The reaction iscarried out at a temperature of about 80° C. to 120° C. for a period oftime to ensure the completion of the reaction. In a further aspect, thetreatment with the acid is with hydrochloric acid at a temperature ofabout 0° C. to 40° C. for a period of time to ensure the completion ofthe reaction. Compound 7.1 can be synthesized following the reactionconditions shown above in Scheme VI.

9. Reaction Scheme IX

Alternatively, one can prepare the bicyclic pyrazole analogues of type1.2 by reaction shown in Scheme IX below. For example, a compoundrepresented by compound 9.1 can be prepared by reacting a compoundrepresented by compound 7.1 with an appropriate boronate reagent in thepresence of a Grignard reagent and in an inert solvent. In one aspect,the boronate reagent can be trimethyl borate, the Grignard reagent isisopropylmagnesium chloride lithium chloride complex and the inertsolvent can be tetrahydrofuran. The reaction is carried out at atemperature of about −78° C. to 25° C. for a period of time to ensurethe completion of the reaction. Compound 7.1 can be synthesizedfollowing the reaction conditions shown above in Scheme VI.

A compound represented by compound 9.2 can be prepared by reacting acompound represented by compound 9.1 with a suitable peroxide agent inthe presence of an appropriate base in a suitable inert solvent at atemperature of about 0° C. and 40° C. for a period of time to ensure thecompletion of the reaction. In one aspect, the peroxide agent ishydrogen peroxide, the base is sodium hydroxide and the inert solvent istetrahydrofuran.

A compound represented by compound 1.2 can be prepared by reacting acompound represented by compound 9.2 with an appropriate alkylatingreagent and a suitable base in a suitable inert solvent at a temperatureof about 0° C. and 40° C. for a period of time to ensure the completionof the reaction. In one aspect, the alkylating reagent is iodomethane,the base is cesium carbonate and the inert solvent isN,N-dimethylformamide.

In a further aspect, the compound produced exhibits positive allostericmodulation of mGluR5 response to glutamate as an increase in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5.

In a further aspect, the compound produced exhibits positive allostericmodulation of mGluR5 (e.g., rmGluR5) with an EC₅₀ of less than about10,000 nM, of less than about 5,000 nM, of less than about 1,000 nM, ofless than about 500 nM, or of less than about 100 nM. In a still furtheraspect, the compound produced exhibits potentiation of mGluR5 responseto glutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with human mGluR5(H10H cell line) in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. In a yet furtheraspect, the compound produced exhibits positive allosteric modulation ofmGluR5 (e.g., hmGluR5) with an EC₅₀ of less than about 10,000 nM, ofless than about 5,000 nM, of less than about 1,000 nM, of less thanabout 500 nM, or of less than about 100 nM.

In particular, the compound produced exhibits activity in potentiatingthe mGluR5 receptor in the disclosed assays, generally with an EC₅₀ forpotentiation of less than about 10 μM. Preferred compounds within thepresent invention had activity in potentiating the mGluR5 receptor withan EC₅₀ for potentiation of less than about 500 nM. Preferred compoundsfurther caused a leftward shift of the agonist EC₅₀ by greater than3-fold. These compounds did not cause mGluR5 to respond in the absenceof agonist, and they did not elicit a significant increase in themaximal response of mGluR5 to agonists. These compounds are positiveallosteric modulators (potentiators) of human and rat mGluR5 and wereselective for mGluR5 compared to the other seven subtypes ofmetabotropic glutamate receptors.

It is contemplated that each disclosed methods can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed methods can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

Table 1 below lists specific compounds as well as experimentallydetermined mGluR5 activity determined in a cell-based assay. The mGluR5activity was determined using the metabotropic glutamate receptoractivity assays in human embryonic kidney cells as described herein,wherein the human embryonic kidney cells were transfected with humanmGluR5. The compounds in Table 1 were synthesized with methods identicalor analogous to those shown herein. The requisite starting materialswere commercially available, described in the literature, or readilysynthesized by one skilled in the art of organic synthesis.

TABLE I EC₅₀ No. Structure* pEC50 E_(max) (nM) 1

6.79 67    161 2

6.70 76    201 3

6.77 66    169 4

6.38 70    414 5

7.10 50   79.6 6

6.53 74    292 7

6.39 58    406 8

6.68 78    208 9

6.59 72    257 10

6.57 69    269 11

6.56 82    273 12

6.49 69    322 13

6.23 75    587 14

<5.00 51 >10,000 15

<4.52 30 >30,200 16

6.76 77    172 17

6.17 81    673 18

6.59 66    256 19

5.91 72    1,067 20

5.53 65    2,950 21

5.89 77    1,281 22

5.53 34    2,907 23

5.82 58    1,372 24

5.51 58    3,026 25

6.34 60    457 26

7.08 52    83 27

<4.52 23 >30,200 28

5.78 81    1,660 29

<5.00 47 >10,000 30

6.48 59    331 31

6.77 54    170 32

5.75 23    1,778 33

5.98 71    1,047 34

5.52 60    3,020 35

<4.52 36 >30,200 36

<5.00 39 >10,000 37

<4.52 12 >30,200 38

6.53 58    295 39

6.68 55    209 40

6.15 58    708 41

6.79 74    162 42

6.86 69    138 43

6.25 72    562 44

6.16 66    692 45

6.62 75    240 46

<4.52 35 >30,200 47

5.97 52    1,072 48

6.31 67    490 49

5.56 52    2,754 50

6.36 59    437 51

6.12 56    759 52

<5.00 69 >10,000 53

5.58 67    2,630 54

<4.52 25 >30,200 55

5.53 23    2,951 56

6.26 62    550 57

5.52 44    3,020 58

5.34 51    4,571 59

5.74 15    1,820 *Note: “*R” and “*S” indicates that an enantiomericallypure compound was isolated with “R” and “S” arbitrarily assigned todistinguish the enantiomers; absolute configuration was not determined.

E. Pharmaceutical Compositions

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound or at least one product of adisclosed method and a pharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require negative allosteric modulationof metabotropic glutamate receptor activity an appropriate dosage levelwill generally be about 0.01 to 500 mg per kg patient body weight perday and can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably 0.5 to 100 mg/kg per day. A suitable dosage level can beabout 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, orabout 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the from of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage of the patient to be treated. Thecompound can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosing regimen can be adjusted toprovide the optimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for modulating glutamate receptor activity(e.g., treatment of one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction) in mammals (e.g., humans)comprising combining one or more disclosed compounds, products, orcompositions with a pharmaceutically acceptable carrier or diluent.Thus, in one aspect, the invention relates to a method for manufacturinga medicament comprising combining at least one disclosed compound or atleast one disclosed product with a pharmaceutically acceptable carrieror diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

F. Methods of Using the Compounds and Compositions

The amino acid L-glutamate (referred to herein simply as glutamate) isthe principal excitatory neurotransmitter in the mammalian centralnervous system (CNS). Within the CNS, glutamate plays a key role insynaptic plasticity (e.g., long term potentiation (the basis of learningand memory)), motor control and sensory perception. It is now wellunderstood that a variety of neurological and psychiatric disorders,including, but not limited to, schizophrenia general psychosis andcognitive deficits, are associated with dysfunctions in theglutamatergic system. Thus, modulation of the glutamatergic system is animportant therapeutic goal. Glutamate acts through two distinctreceptors: ionotropic and metabotropic glutamate receptors. The firstclass, the ionotropic glutamate receptors, is comprised of multi-subunitligand-gated ion channels that mediate excitatory post-synapticcurrents. Three subtypes of ionotropic glutamate receptors have beenidentified, and despite glutamate serving as agonist for all threereceptor subtypes, selective ligands have been discovered that activateeach subtype. The ionotropic glutamate receptors are named after theirrespective selective ligands: kainite receptors, AMPA receptors and NMDAreceptors.

The second class of glutamate receptor, termed metabotropic glutamatereceptors, (mGluRs), are G-protein coupled receptors (GPCRs) thatmodulate neurotransmitter release or the strength of synaptictransmission, based on their location (pre- or post-synaptic). ThemGluRs are family C GPCR, characterized by a large (˜560 amino acid)“venus fly trap” agonist binding domain in the amino-terminal domain ofthe receptor. This unique agonist binding domain distinguishes family CGPCRs from family A and B GPCRs wherein the agonist binding domains arelocated within the 7-strand transmembrane spanning (7TM) region orwithin the extracellular loops that connect the strands to this region.To date, eight distinct mGluRs have been identified, cloned andsequenced. Based on structural similarity, primary coupling tointracellular signaling pathways and pharmacology, the mGluRs have beenassigned to three groups: Group I (mGluR1 and mGluR5), Group II (mGluR2and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8). Group ImGluRs are coupled through Gαq/11 to increase inositol phosphate andmetabolism and resultant increases in intracellular calcium. Group ImGluRs are primarily located post-synaptically and have a modualtoryeffect on ion channel activity and neuronal excitability. Group II(mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8)mGluRs are primarily located pre-synaptically where they regulate therelease of neurotransmitters, such as glutamate. Group II and Group IIImGluRs are coupled to Gαi and its associated effectors such as adenylatecyclase.

Post-synaptic mGluRs are known to functionally interact withpost-synaptic ionotropic glutamate receptors, such as the NMDA receptor.For example, activation of mGluR5 by a selective agonist has been shownto increase post-synaptic NMDA currents (Mannaioni et. al. J. Neurosci.21:5925-5934 (2001)). Therefore, modulation of mGluRs is an approach tomodulating glutamatergic transmission. Numerous reports indicate thatmGluR5 plays a role in a number of disease states including anxiety(Spooren et. al. J. Pharmacol. Exp. Therapeut. 295:1267-1275 (2000),Tatarczynska et al. Br. J. Pharmaol. 132:1423-1430 (2001)),schizophrenia (reviewed in Chavez-Noriega et al. Curr. Drug Targets: CNS& Neurological Disorders 1:261-281 (2002), Kinney, G. G. et al. J.Pharmacol. Exp. Therapeut. 313:199-206 (2005)), addiction to cocaine(Chiamulera et al. Nature Neurosci. 4:873-874 (2001), Parkinson'sdisease (Awad et al. J. Neurosci. 20:7871-7879 (2000), Ossowska et al.Neuropharmacol. 41: 413-420 (2001), and pain (Salt and Binns Neurosci.100:375-380 (2001).

Phencyclidine (PCP) and other NMDA receptor antagonists induce apsychotic state in humans similar to schizophrenia. In schizophreniapatients, PCP and ketamine exacerbate/precipitate preexisting positiveand negative symptoms in stable patients. Treatment with NMDA receptorco-agonists can improve positive and negative symptoms. A schematic ofthe NMDA receptor is shown in FIG. 1. Activation of mGluR5 potentiatesNMDA receptor function as shown in FIG. 2. Orthosteric ligands lacksubtype selectivity and can cause unwanted side effects. Allostericmodulators (see FIG. 3) that can target transmembrane domains offer apharmacologically attractive alternative. In one aspect, transmembranedomains can be significantly less conserved than extracellular loopregions.

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formula I or the otherdrugs have utility, where the combination of drugs together are safer ormore effective than either drug alone. The other drug(s) can beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound will be more efficacious than either as a singleagent.

In one aspect, the subject compounds can be coadministered withanti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, muscarinic agonists, muscarinic potentiators HMG-CoAreductase inhibitors, NSAIDs and anti-amyloid antibodies.

In another aspect, the subject compounds can be administered incombination with sedatives, hypnotics, anxiolytics, antipsychotics,selective serotonin reuptake inhibitors (SSRIs), monoamine oxidaseinhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the likesuch as, but not limited to: risperidone, clozapine, haloperidol,fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and saltsthereof and combinations thereof.

In another aspect, the subject compound can be used in combination withlevodopa (with or without a selective extracerebral decarboxylaseinhibitor), anitcholinergics such as biperiden, COMT inhibitors such asentacapone, A2a adenosine antagonists, cholinergic agonists, NMDAreceptor antagonists and dopamine agonists.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction.

Examples of disorders associated with glutamate dysfunction include:autism, acute and chronic neurological and psychiatric disorders such ascerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, ocular damage, retinopathy,cognitive disorders, idiopathic and drug-induced Parkinson's disease,muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine (including migraineheadache), urinary incontinence, substance tolerance, addictivebehavior, including addiction to substances (including opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), withdrawal from such addictive substances(including substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity,psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), mooddisorders (including depression, mania, bipolar disorders), trigeminalneuralgia, hearing loss, tinnitus, macular degeneration of the eye,emesis, brain edema, pain (including acute and chronic pain states,severe pain, intractable pain, neuropathic pain, and post-traumaticpain), tardive dyskinesia, sleep disorders (including narcolepsy),attention deficit/hyperactivity disorder, and conduct disorder.

Epilepsy can be treated or prevented by the compositions disclosedherein, including absence epilepsy. In various aspects, thecompositisions disclosed herein can have a protective role for spike andwave discharges associated with absence seizures. Metabotropic glutamate(mGlu) receptors positioned at synapses of the cortico-thalamo-corticalcircuitry that generates spike-and-wave discharges (SWDs) associatedwith absence seizures. Thus, without wishing to be bound by a particulartheory, mGluR receptors are therapeutic targets for the treatment ofabsence epilepsy (e.g. see Epilepsia, 52(7): 1211-1222, 2011;Neuropharmacology 60 (2011) 1281e1291; and abstract from 7thInternational conference on metabotropic glutamate receptors, Oct. 2-6,2011 Taormina, Italy, “Pharmacological activation of metabotropicglutamate receptor subtype reduces Spike and Wave Discharges in theWAG/Rij rat model of absence epilepsy,” I. Santolini, V. D'Amore, C. M.van Rijn, A. Simonyi, A, Prete, P. J. Conn, C. Lindsley, S. Zhou, P. N.Vinson, A. L. Rodriguez, C. K. Jones, S. R. Stauffer, F. Nicoletti, G.van Luijtelaar and R. T. Ngomba).

Anxiety disorders that can be treated or prevented by the compositionsdisclosed herein include generalized anxiety disorder, panic disorder,and obsessive compulsive disorder. Addictive behaviors include addictionto substances (including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Thus, in some aspects of the disclosed method, the disorder is dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including positive and negative symptoms thereof andcognitive dysfunction related to schizophrenia, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression.

Thus, provided is a method for treating or prevention schizophrenia,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding schizophrenia and related disorders.

Also provided is a method for treating or prevention anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder and anxiety disorder not otherwisespecified.

a. Treatment of a Neurological and/or Psychiatric Disorder Associatedwith Glutamate Dysfunction

In one aspect, the invention relates to a method for the treatment of adisorder associated with mGluR5 activity in a mammal comprising the stepof administering to the mammal at least one disclosed compound or atleast one disclosed product in a dosage and amount effective to treatthe disorder in the mammal. In a further aspect, the mammal is a human.In a further aspect, the mammal has been diagnosed with a need fortreatment of the disorder prior to the administering step. In a furtheraspect, the method further comprises the step of identifying a mammal inneed of treatment of the disorder.

In one aspect, the invention relates to a method for the treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal comprising the step of administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method for thetreatment of a neurological and/or psychiatric disorder associated withglutamate dysfunction in a mammal comprising the step of administeringto the mammal a therapeutically effective amount of at least onecompound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In a further aspect, the method furthercomprises the step of identifying a mammal in need of treatment of thedisorder.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder associated with mGluR5 dysfunction. In a further aspect, thedisorder is selected from autism, dementia, delirium, amnesticdisorders, age-related cognitive decline, schizophrenia, including thepositive and negative symptoms thereof and cognitive dysfunction relatedto schizophrena, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,including absence epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

b. Treatment of a Disorder of Uncontrolled Cellular Proliferation

In one aspect, the invention relates to a method for the treatment of adisorder of uncontrolled cellular proliferation in a mammal comprisingthe step of administering to the mammal a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method for thetreatment of a disorder of uncontrolled cellular proliferation in amammal comprising the step of administering to the mammal atherapeutically effective amount of at least one compound having astructure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In a further aspect, the method furthercomprises the step of identifying a mammal in need of treatment of thedisorder. In a yet further aspect, the disorder of uncontrolled cellularproliferation is associated with mGluR5 dysfunction.

In a further aspect, the disorder of uncontrolled cellular proliferationis cancer. In a further aspect, the disorder is cancer. In a stillfurther aspect, the cancer is selected from breast cancer, renal cancer,gastric cancer, and colorectal cancer. In a further aspect, the disorderis selected from lymphoma, cancers of the brain, genitourinary tractcancer, lymphatic system cancer, stomach cancer, larynx cancer, lung,pancreatic cancer, breast cancer, and malignant melanoma.

c. Potentiation of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for potentiation ofmGluR5 activity in a mammal comprising the step of administering to themammal at least one disclosed compound or at least one disclosed productin a dosage and amount effective to increase mGluR5 activity in themammal either in the presence or absence of the endogenous ligand. In afurther aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for increasing mGluR5 activity prior tothe administering step. In a further aspect, the mammal has beendiagnosed with a need for treatment of a disorder related to mGluR5activity prior to the administering step. In a further aspect, themethod further comprises the step of identifying a mammal in need ofincreasing mGluR5 activity.

In one aspect, the invention relates to a method for potentiation ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method forpotentiation of metabotropic glutamate receptor activity in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In a further aspect, the method furthercomprises the step of identifying a mammal in need of treatment of thedisorder. In a further aspect, the metabotropic glutamate receptor ismGluR5. In a yet further aspect, the increase in mGluR5 activity treatsa disorder associated with mGluR5 activity in the mammal. In a stillfurther aspect, the mammal has been diagnosed with a need for treatmentof the disorder prior to the administering step. In an even furtheraspect, treatment further comprises the step of identifying a mammal inneed of treatment of the disorder.

In a further aspect, potentiation of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mGluR5 dysfunction. In afurther aspect, the disorder is selected from autism, dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including the positive and negative symptoms thereof andcognitive dysfunction related to schizophrena, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, including absence epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, psychoticdepression, autism, panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, post-traumatic stress disorder,acute stress disorder, generalized anxiety disorder, anxiety disorderdue to a general medical condition, and substance-induced anxietydisorder. In an even further aspect, the disorder is absence epilepsy.In a still further aspect, the disorder is selected from cognitivedisorders, age-related cognition decline, learning deficit, intellectualimpairment disorders, cognition impairment in schizophrenia, cognitionimpairment in Alzheimer's disease, and mild cognitive impairment.

In a further aspect, potentiation of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In a further aspect, the disorder is selected fromlymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,breast cancer, and malignant melanoma.

d. Partial Agonism of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal. In a furtheraspect, the method relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal by contacting atleast one cell in the mammal, comprising the step of contacting the atleast one cell with at least one disclosed compound or at least onedisclosed product in an amount effective to inhibit mGluR5 activity inthe at least one cell.

In one aspect, the invention relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method forpartial agonism of metabotropic glutamate receptor activity in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for partial agonism of metabotropicglutamate receptor activity prior to the administering step. In a stillfurther aspect, the method further comprises the step of identifying amammal in need for partial agonism of metabotropic glutamate receptoractivity. In a yet further aspect, the metabotropic glutamate receptoris mGluR5.

In a further aspect, partial agonism of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mGluR5 dysfunction. In afurther aspect, the disorder is selected from autism, dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including the positive and negative symptoms thereof andcognitive dysfunction related to schizophrena, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, including absence epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, psychoticdepression, autism, panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, post-traumatic stress disorder,acute stress disorder, generalized anxiety disorder, anxiety disorderdue to a general medical condition, and substance-induced anxietydisorder. In an even further aspect, the disorder is absence epilepsy.In a still further aspect, the disorder is selected from cognitivedisorders, age-related cognition decline, learning deficit, intellectualimpairment disorders, cognition impairment in schizophrenia, cognitionimpairment in Alzheimer's disease, and mild cognitive impairment.

In a further aspect, partial agonism of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In a further aspect, the disorder is selected fromlymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,breast cancer, and malignant melanoma.

e. Enhancing Cognition

In one aspect, the invention relates to a method for enhancing cognitionin a mammal comprising the step of administering to the mammal aneffective amount of at least one disclosed compound.

In one aspect, the invention relates to a method for enhancing cognitionin a mammal comprising the step of administering to the mammal aneffective amount of at least one compound having a structure representedby a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method forenhancing cognition in a mammal comprising the step of administering tothe mammal an effective amount of at least one compound having astructure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the cognitionenhancement is a statistically significant increase in Novel ObjectRecognition. In a further aspect, the cognition enhancement is astatistically significant increase in performance of the Wisconsin CardSorting Test. In a still further aspect, the compound is administeredfor cognition enhancement in a subject with a disorder selected fromcognitive disorders, age-related cognition decline, learning deficit,intellectual impairment disorders, cognition impairment inschizophrenia, cognition impairment in Alzheimer's disease, and mildcognitive impairment.

f. Modulating mGluR5 Activity in Mammals

In one aspect, the invention relates to a method for modulating mGluR5activity in a mammal comprising the step of administering to the mammalan effective amount of at least one disclosed compound.

In one aspect, the invention relates to a method for modulating mGluR5activity in a mammal comprising the step of administering to the mammalan effective amount of at least one compound having a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method formodulating mGluR5 activity in a mammal comprising the step ofadministering to the mammal an effective amount of at least one compoundhaving a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for modulating mGluR5 activity prior tothe administering step. In a further aspect, the mammal has beendiagnosed with a need for treatment of a disorder related to mGluR5activity prior to the administering step. In a further aspect, themethod further comprises the step of identifying a mammal in need ofincreasing mGluR5 activity.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In one aspect, an effective amount is a therapeutically effectiveamount.

In one aspect, modulating mGluR5 activity in a mammal is associated withthe treatment of a neurological and/or psychiatric disorder associatedwith mGluR5 dysfunction. In a further aspect, the disorder is selectedfrom autism, dementia, delirium, amnestic disorders, age-relatedcognitive decline, schizophrenia, including the positive and negativesymptoms thereof and cognitive dysfunction related to schizophrena,psychosis including schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,substance-related disorder, movement disorders, epilepsy, includingabsence epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity,eating disorders, brain edema, sleep disorder, narcolepsy, anxiety,affective disorder, panic attacks, unipolar depression, bipolardisorder, and psychotic depression. In a yet further aspect, thedisorder is selected from dementia, delirium, amnestic disorders,age-related cognitive decline, schizophrenia, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, psychotic depression, autism,panic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobia, social phobia, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, and substance-induced anxiety disorder. In an even furtheraspect, the disorder is absence epilepsy. In a still further aspect, thedisorder is selected from cognitive disorders, age-related cognitiondecline, learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In one aspect, modulating mGluR5 activity in a mammal is associated withthe treatment of a disorder associated with uncontrolled cellularproliferation. In a further aspect, the disorder is cancer. In a stillfurther aspect, the cancer is selected from breast cancer, renal cancer,gastric cancer, and colorectal cancer. In a further aspect, the disorderis selected from lymphoma, cancers of the brain, genitourinary tractcancer, lymphatic system cancer, stomach cancer, larynx cancer, lung,pancreatic cancer, breast cancer, and malignant melanoma.

g. Modulating mGluR5 Activity in Cells

In one aspect, the invention relates to a method for modulating mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with an effective amount of at least one disclosedcompound.

In one aspect, the invention relates to a method for modulating mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with an effective amount of at least one compound havinga structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In various further aspects, the invention relates to a method formodulating mGluR5 activity in at least one cell, comprising the step ofcontacting the at least one cell with an effective amount of at leastone compound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In one aspect, the cell is mammalian. In a further aspect, the cell ishuman. In a further aspect, the cell has been isolated from a mammalprior to the contacting step.

In a further aspect, contacting is via administration to a mammal. In afurther aspect, the mammal has been diagnosed with a need for modulatingmGluR5 activity prior to the administering step. In a further aspect,the mammal has been diagnosed with a need for treatment of a disorderrelated to mGluR5 activity prior to the administering step.

2. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for potentiation of metabotropic glutamate receptoractivity in a mammal comprising combining a therapeutically effectiveamount of a disclosed compound or product of a disclosed method with apharmaceutically acceptable carrier or diluent.

3. Use of Compounds

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method. In a further aspect, a use relatesto the manufacture of a medicament for the treatment of a disorderassociated with glutamate dysfunction in a mammal. In a further aspect,the disorder is a neurological and/or psychiatric disorder. In a furtheraspect, the disorder is a disease of uncontrolled cellularproliferation. In a further aspect, a use relates to treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal.

In a further aspect, a use relates to potentiation of metabotropicglutamate receptor activity in a mammal. In a further aspect, a userelates to partial agonism of metabotropic glutamate receptor activityin a mammal. In a further aspect, a use relates to enhancing cognitionin a mammal. In a further aspect, a use relates to modulating mGluR5activity in a mammal. In a further aspect, a use relates to modulatingmGluR5 activity in a cell.

In one aspect, a use is treatment of a neurological and/or psychiatricdisorder associated with mGluR5 dysfunction. In a further aspect, thedisorder is selected from autism, dementia, delirium, amnesticdisorders, age-related cognitive decline, schizophrenia, including thepositive and negative symptoms thereof and cognitive dysfunction relatedto schizophrena, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,including absence epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, and psychotic depression. In a yet further aspect, thedisorder is selected from dementia, delirium, amnestic disorders,age-related cognitive decline, schizophrenia, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, psychotic depression, autism,panic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobia, social phobia, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, and substance-induced anxiety disorder. In an even furtheraspect, the disorder is absence epilepsy. In a still further aspect, thedisorder is selected from cognitive disorders, age-related cognitiondecline, learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In one aspect, a use is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In a further aspect, the disorder is selected fromlymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,breast cancer, and malignant melanoma.

In one aspect, the invention relates to the use of a disclosed compoundor a disclosed product in the manufacture of a medicament for thetreatment of a disorder associated with glutamate dysfunction in amammal. In a further aspect, the disorder is a neurological and/orpsychiatric disorder. In a further aspect, the disorder is a disease ofuncontrolled cellular proliferation.

4. Kits

In one aspect, the invention relates to a kit comprising a disclosedcompound or a product of a disclosed method and one or more of at leastone agent known to increase mGluR5 activity; at least one agent known todecrease mGluR5 activity; at least one agent known to treat aneurological and/or psychiatric disorder; at least one agent known totreat a disease of uncontrolled cellular proliferation; or instructionsfor treating a disorder associated with glutamate dysfunction. In afurther aspect, the at least one compound or the at least one productand the at least one agent are co-formulated. In a further aspect, theat least one compound or the at least one product and the at least oneagent are co-packaged.

In a further aspect, the kit comprises a disclosed compound or a productof a disclosed method.

In a further aspect, the at least one compound and the at least oneagent are co-formulated. In a still further aspect, the at least onecompound and the at least one agent are co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is contemplated that the disclosed kits can be used in connectionwith the disclosed methods of making, the disclosed methods of using,and/or the disclosed compositions.

5. Non-Medical Uses

Also provided are the uses of the disclosed compounds and products aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR. In a further aspect, the inventionrelates to the use of a disclosed compound or a disclosed product aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR5 related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR5.

G. Experimental

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. The Examples aretypically depicted in free base form, according to the IUPAC namingconvention. However, some of the Examples were obtained or isolated insalt form.

As indicated, some of the Examples were obtained as racemic mixtures ofone or more enantiomers or diastereomers. The compounds may be separatedby one skilled in the art to isolate individual enantiomers. Separationcan be carried out by the coupling of a racemic mixture of compounds toan enantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. A racemicor diastereomeric mixture of the compounds can also be separateddirectly by chromatographic methods using chiral stationary phases.

1. General Methods

¹H NMR spectra were recorded either on a Bruker DPX-400 or on a BrukerAV-500 spectrometer with standard pulse sequences, operating at 400 MHzand 500 MHz respectively. Chemical shifts (δ) are reported in parts permillion (ppm) downfield from tetramethylsilane (TMS), which was used asinternal standard.

Microwave assisted reactions were performed in a single-mode reactor:Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currentlyBiotage).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Open column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)under standard techniques. Flash column chromatography was performedusing ready-to-connect cartridges from Merck, on irregular silica gel,particle size 15-40 μm (normal layer disposable flash columns) on a SPOTor FLASH system from Armen Instrument.

Melting point values are peak values, and are obtained with experimentaluncertainties that are commonly associated with this analytical method.For a number of compounds, melting points were determined in opencapillary tubes either on a Mettler FP62 or on a Mettler FP81HT-FP90apparatus. Melting points were measured with a temperature gradient of10° C./minute. Maximum temperature was 300° C. The melting point wasread from a digital display.

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with asodium lamp and reported as follows: [α]° (λ, c g/100 ml, solvent, T°C.). [α]_(λ) ^(T)=(100α)/(l×c): where l is the path length in dm and cis the concentration in g/100 ml for a sample at a temperature T (° C.)and a wavelength λ (in nm). If the wavelength of light used is 589 nm(the sodium D line), then the symbol D might be used instead. The signof the rotation (+ or −) should always be given. When using thisequation the concentration and solvent are always provided inparentheses after the rotation. The rotation is reported using degreesand no units of concentration are given (it is assumed to be g/100 ml).

2. LCMS Methods

a. General Procedure A

The HPLC measurement was performed using an HP 1100 (AgilentTechnologies) system comprising a pump (quaternary or binary) withdegasser, an autosampler, a column oven, a diode-array detector (DAD)and a column as specified in the respective methods below. Flow from thecolumn was split to the MS spectrometer. The MS detector was configuredwith either an electrospray ionization source or an ESCI dual ionizationsource (electrospray combined with atmospheric pressure chemicalionization). Low-resolution mass spectra were acquired either on asingle quadrupole (SQD) detector or Time of Flight (TOF) detector byscanning from 100 to 1000 in 0.1 second using an inter-channel delay of0.08 second or scanning from 100 to 750 in 0.5 seconds using a dwelltime of 0.3 seconds (TOF). The capillary needle voltage was 3.0 kV (SQD)or 2.5 kV for positive ionization mode and 2.9 kV for negativeionization mode (TOF). The source temperature was maintained at 140° C.Nitrogen was used as the nebulizer gas. Data acquisition was performedwith MassLynx-Openlynx software

b. General Procedure B

The UPLC (Ultra Performance Liquid Chromatography) measurement wasperformed using an Acquity UPLC (Waters) system comprising a samplerorganizer, a binary pump with degasser, a four column's oven, adiode-array detector (DAD) and a column as specified in the respectivemethods. Flow from the column was brought to the MS spectrometer. The MSdetector was configured with an electrospray ionization source.Low-resolution mass spectra were acquired on a single quadrupole (SQD)detector by scanning from 100 to 1000 in 0.1 second using aninter-channel delay of 0.08 second. The capillary needle voltage was 3.0kV. The source temperature was maintained at 140° C. Nitrogen was usedas the nebulizer gas. Data acquisition was performed withMassLynx-Openlynx software.

c. LCMS Method 1

In addition to the general procedure B: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 mL/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/L ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 3.8minutes, to 5% A, 95% B in 4.6 minutes, kept till 5.0 minutes. Injectionvolume 2.0 μL. Low-resolution mass spectra (single quadrupole, SQDdetector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

d. LCMS Method 2

In addition to the general procedure A: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μm, 2.1×30 mm) from Agilent, witha flow rate of 1.0 mL/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (mixture of acetonitrile/methanol, 1/1),to 100% B in 5.0 minutes, kept till 5.15 minutes and equilibrated toinitial conditions at 5.30 minutes until 7.0 minutes. Injection volume 2μL. Low-resolution mass spectra (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 second using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 20 V for positive ionization mode and 30 V fornegative ionization mode.

e. LCMS Method 3

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Eclipse Plus-C18 column (3.5 μm, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. The gradient conditions used are:95% A (0.5 g/l ammonium acetate solution+5% acetonitrile), 5% B(acetonitrile) to 100% B in 5.0 minutes, kept till 5.15 minutes andequilibrated to initial conditions at 5.3 minutes until 7.0 minutes.Injection volume 2 μl. High-resolution mass spectra (Time of Flight, TOFdetector) were acquired by scanning from 100 to 750 in 0.5 seconds usinga dwell time of 0.3 seconds. The capillary needle voltage was 2.5 kV forpositive ionization mode and 2.9 kV for negative ionization mode. Thecone voltage was 20 V for both positive and negative ionization modes.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

f. LCMS Method 4

In addition to the general procedure B: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μm, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (mixture of acetonitrile/methanol, 1/1),to 100% B at 6.5 minutes, kept till 7.0 minutes and equilibrated toinitial conditions at 7.3 minutes until 9.0 minutes. Injection volume 2μl. Low-resolution mass spectra (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 seconds using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 20 V for positive ionization mode and 30 V fornegative ionization mode.

g. LCMS Method 5

Same gradient as LCMS Method 1; column used: RRHD Eclipse Plus-C18 (1.8μm, 2.1×50 mm) from Agilent.

h. LCMS Method 6

In addition to the general procedure B: Reversed phase UPLC was carriedout on a Eclipse Plus-C18 (1.8 μm, 2.1×50 mm) from Agilent, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (6.5 mM ammonium acetate inH₂O/acetonitrile 95/5), 5% B (acetonitrile), to 40% A, 60% B in 7.0minutes, to 5% A, 95% B in 8.6 minutes, kept till 9.0 minutes. Injectionvolume 2.0 μl. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

3. 1-(3-tert-butoxycarbonylaminoethyl)-1H-pyrazole-3,5-dicarboxylic aciddiethyl ester

2-(2-tert-Butoxycarbonylamino)ethylbromide (1.7 g, 7.8 mmol) was addedto a stirred suspension of diethyl 3,5-pyrazoledicarboxylate (1.5 g, 7.0mmol) and Cs₂CO₃ (2.8 g, 8.5 mmol) in DMF (60 mL). The mixture wasstirred at room temperature for 16 hours and the solvent evaporated invacuo. The solid was washed with DCM and the filtrate evaporated invacuo to yield1-(3-tert-butoxycarbonylaminoethyl)-1H-pyrazole-3,5-dicarboxylic aciddiethyl ester (2.87 g, quantitative yield) as a white solid that wasused in the next step without further purification. C₁₆H₂₅N₃O₆ LCMS: Rt1.60, m/z 356 [M+H]⁺ (see LCMS Method 1).

4. 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acidethyl ester

1-(3-tert-Butoxycarbonylaminoethyl)-1H-pyrazole-3,5-dicarboxylic aciddiethyl ester (2.4 g, 6.7 mmol) was dissolved in a 4N solution of HCl indioxane (25 mL) under N₂. The mixture was stirred at room temperaturefor 1 hour and then basified with a saturated solution of Na₂CO₃ andextracted with DCM. The organic layer was separated, washed with brine,dried (Na₂SO₄), filtered and the solvent evaporated in vacuo. The crudeproduct was purified by flash column chromatography (silica; 7 Msolution of ammonia in MeOH in DCM 0/100 to 5/95). The desired fractionswere collected and the solvents evaporated in vacuo to yield4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethylester (1.1 g, 79% yield) as a white solid. C₉H₁₁N₃O₃ LCMS: Rt 0.49, m/z210 [M+H]⁺ (see LCMS Method 1).

5.4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid ethyl ester

A 60% dispersion of sodium hydride in mineral oils (0.16 g, 4.0 mmol)was added to a stirred solution of4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethylester (0.7 g, 3.35 mmol) in DMF (14 mL) at 0° C. The mixture was stirredat room temperature for 1 hour and then benzyl bromide (0.48 mL, 4.0mmol) was added. The mixture was stirred at room temperature for 16hours, diluted with H₂O and extracted with DCM. The organic layer wasseparated, washed with brine, dried (NaSO₄), filtered and the solventsevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; AcOEt in DCM 0/100 to 50/50). The desiredfractions were collected and the solvents evaporated in vacuo to yield4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid ethyl ester (0.83 g, 83% yield) as a white oil. C₁₆H₁₇N₃O₃ LCMS: Rt1.79, m/z 300 [M+H]⁺ (see LCMS Method 1).

6.4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol

A 1M solution of lithium aluminum hydride in THF (6.5 mL, 6.5 mmol) wasadded dropwise to a stirred solution of4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid ethyl ester (0.81 g, 2.7 mmol) in THF (16 mL) under N₂ at 0° C. Thereaction mixture was stirred at room temperature for 30 minutes,quenched with MeOH and the solvents evaporated in vacuo. The crudeproduct was purified by flash column chromatography (silica; 7 Msolution of ammonia in methanol in DCM 0/100 to 10/90). The desiredfractions were collected and the solvents evaporated in vacuo to yield4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol(0.67 g, 100% yield) as a colorless oil. C₁₄H₁₇N₃O LCMS: Rt 1.25, m/z244 [M+H]⁺ (see LCMS Method 1).

7.4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine

Di-tert-butyl azodicarboxylate (0.76 g, 3.3 mmol) was added to a stirredsolution of triphenylphosphine (0.87 g, 3.3 mmol), phenol (0.31 g, 3.3mmol) and4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol(1.2 mL, 2.75 mmol) in THF (0.6 mL) in a sealed tube and under N₂. Themixture was stirred at 120° C. for 20 minutes under microwaveirradiation and the solvents were evaporated in vacuo. The crude productwas purified by flash column chromatography (silica; AcOEt in DCM 0/100to 50/50). The desired fractions were collected and the solvents wereevaporated in vacuo to yield4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine(0.65 g, 74% yield) as a colorless oil that precipitated upon standing.C₂₀H₂₁N₃O LCMS: Rt 3.03, m/z 320 [M+H]⁺ (see LCMS Method 1).

8. 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

10% Palladium on charcoal (0.21 g, 0.2 mmol) was added to a stirredsuspension of4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine(0.65 g, 2.0 mmol) and ammonium formate (0.38 g, 6.1 mmol) in MeOH (14mL) in a sealed tube under N₂. The mixture was stirred at 90° C. for 1hour, filtered through a pad of diatomaceous earth and washed with DCM.The solvents were evaporated in vacuo to yield4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.58 g,66% yield) as a clear oil that was used in the next step without furtherpurification. C₁₃H₁₅N₃O LCMS: Rt 1.19, m/z 230 [M+H]⁺ (see LCMS Method1).

9. 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester

Sodium (6.74 g, 293 mmol) was added to EtOH (808 mL) at 0° C. Themixture was stirred at 0° C. until the sodium was completely dissolved.Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. Themixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36mL, 266 mmol) was added. Then the mixture was stirred at roomtemperature for 16 hours and the solvent was evaporated in vacuo. Theresidue was dissolved in H₂O and the mixture was acidified with a 1Msolution of HCl and extracted with DCM. The organic layer was separated,dried (Na₂SO₄), filtered and the solvents evaporated in vacuo. The crudeproduct was purified by open column chromatography (silica; DCM) toyield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.9 g, 54% yield)as an oil.

10. 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester

Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solutionof 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol) inEtOH (3 mL). The mixture was stirred at 80° C. for 16 hours and thesolvent was evaporated in vacuo. The crude product was purified by flashcolumn chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desiredfractions were collected and the solvents evaporated in vacuo to yield5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98%yield) as a yellow oil.

11.rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester

Di-tert-butyl azodicarboxylate (2.52 g, 10.96 mmol) was added to astirred solution of triphenylphosphine (2.87 g, 10.96 mmol),2-hydroxy-rac-1-methyl-ethyl-carbamic acid tert-butyl ester (2.13 g,12.18 mmol) and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethylester (1.5 g, 6.09 mmol) in THF (45 mL). The mixture was stirred at 120°C. for 20 minutes under microwave irradiation and the solventsevaporated in vacuo. The crude product was purified by open columnchromatography (silica; AcOEt in DCM 0/100 to 10/90). The desiredfractions were collected and the solvents evaporated in vacuo to yieldrac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester (5.58 g, 91% yield, 40% pure) as a colorless oil thatcrystallized upon standing in white crystals.

12.rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

Rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester (5.58 g, 5.53 mmol, 40% pure) was dissolved in a 4Nsolution of HCl in 1,4-dioxane (40 mL) under N₂ at 0° C. The mixture wasstirred at room temperature for 3 hours. The mixture was basified with asaturated solution of Na₂CO₃ and the mixture stirred at room temperaturefor 3 days. Then the mixture was diluted with DCM. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; AcOEt in DCM 0/100 to 70/30). The desired fractions werecollected and the solvents evaporated in vacuo to yieldrac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one(1.52 g, 91% yield) as a white solid.

13.rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

A 1M solution of lithium aluminum hydride in THF (2.14 mL, 2.14 mmol)was added dropwise to a stirred solution ofrac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one(0.5 g, 1.94 mmol) in THF (12 mL) under N₂ at 0° C. The reaction mixturewas stirred at room temperature for 2.5 days and diluted with AcOEt.Na₂SO₄.10H₂O was added at 0° C. and the mixture stirred for 15 minutesat 0° C., filtered through a pad of diatomaceous earth and then washedwith additional AcOEt. The solvents were evaporated in vacuo to yieldrac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine(0.45 g, 84% yield) as an oil that crystallized upon standing, and thatwas used in the next step without further purification.

14.rac-7-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and rac-2-hydroxy-propyl-carbamic acid tert-butyl esterusing the methods described in the preceding examples 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

15.7,7-dimethyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and 2-hydroxy-2-methyl-propyl-carbamic acid tert-butylester using the methods described in the preceding examples 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

16.2-(3-fluoro-phenoxymethyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 1-(3-fluoro-phenoxy)-propan-2-one anddiethyl oxalate using the methods described in the preceding examples 9(2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10(5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

17.5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

4-Fluorobenzoyl chloride (0.14 mL, 1.2 mmol) was added to a stirredsolution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(0.3 g, 1.0 mmol) and pyridine (0.16 mL, 2.0 mmol) in DCM (13 mL) underN₂ at 0° C. The reaction was stirred at room temperature for 1 hour,diluted with a saturated solution of Na₂CO₃ and extracted with DCM. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventsevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; AcOEt in DCM 0/100 to 50/50). The desiredfractions were collected and the solvents evaporated in vacuo. Thedesired product was triturated with DIPE to yield5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(0.21 g, 59% yield) as a white solid. C₂₀H₁₈FN₃O₂ ¹H NMR (500 MHz,CDCl₃) δ ppm 4.07 (br. s., 2H), 4.27 (br. s., 2H), 4.81 (br. s., 2H),5.05 (s, 2H), 6.16 (br. s., 1H), 6.96 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d,J=8.4 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.1, 7.8 Hz, 2H),7.49 (dd, J=8.5, 5.3 Hz, 2H).

18.5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.146 g, 0.38 mmol) was added portionwise to astirred solution of 2-fluorobenzoic acid (0.063 g, 0.45 mmol) in DMF(2.0 mL) at 0° C. The reaction mixture was stirred for 5 minutes andthen DIPEA (0.09 mL, 0.52 mmol) and4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.08 g,0.35 mmol) were added. The reaction mixture was stirred at roomtemperature for 15 hours, diluted with a saturated solution of NH₄Cl andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; AcOEt in DCM 0/100 to30/70). The desired fractions were collected, the solvents evaporated invacuo and the product repurified by flash column chromatography (silica;AcOEt in DCM 0/100 to 70/30). The desired fractions were collected andthe solvents evaporated in vacuo. The residue was suspended in asaturated solution of NH₄Cl, stirred for 1 hour and extracted with DCM.The organic layer was separated, dried (Na₂SO₄), filtered and thesolvents evaporated in vacuo. The product was repurified by reversephase HPLC (gradient from 80% of 0.1% solution of ammoniumformate/ammonium hydroxide buffer pH 9 solution in water and 20% CH₃CNto 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH9 solution in water and 100% CH₃CN) to yield5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(0.050 g, 41% yield) as a clear oil. C₂₀H₁₈FN₃O₂₁H NMR (400 MHz, CDCl₃)δ ppm 3.80 (br. s., 1.1H), 4.22 (br. s., 1.5H), 4.31 (br. s., 1.4H),4.61 (s, 0.9H), 4.99 (s, 1.1H), 5.03 (s, 0.9H), 5.07 (s, 1.1H), 6.07 (s,0.45H), 6.27 (s, 0.55H), 6.90-7.09 (m, 3H), 7.15 (td, J=8.8, 3.6 Hz,1H), 7.21-7.35 (m, 3H), 7.38-7.53 (m, 2H).

19. 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acidethyl ester

1,4-Diazabicylo[2.2.2]octane (1.0 g, 8.93 mmol) and dimethylsulfamoylchloride (0.88 mL, 8.2 mmol) were sequentially added to a solution of5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 8.12mmol) in CH₃CN (10 mL) at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 18 hours. The mixture was diluted with H₂Oand extracted with AcOEt. The organic layer was separated, dried(Na₂SO₄), filtered and the solvents concentrated in vacuo. The crudeproduct was purified by flash column chromatography (silica; AcOEt inheptane 0/100 to 40/60). The desired fractions were collected and thesolvents evaporated in vacuo to yield2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethylester (2.42 g, 84% yield) as a white solid.

20. 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acidmethoxy-methyl-amide

A 2M solution of isopropylmagnesium chloride in THF (1.9 mL, 3.8 mmol)was added to a stirred suspension of2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethylester (0.45 g, 1.27 mmol) and N,O-dimethylhydroxylamine hydrochloride(0.16 g, 1.65 mmol) in DCM (6.5 mL) under nitrogen at −78° C. Themixture was slowly allowed to warm to room temperature and stirred for16 hours. The mixture was diluted with a saturated solution of NH₄Cl andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents were evaporated in vacuo. The crude productwas purified by flash column chromatography (silica; AcOEt in DCM 0/100to 10/90). The desired fractions were collected and the solventsevaporated in vacuo to yield2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acidmethoxy-methyl-amide (0.2 g, 44% yield) as a colourless oil thatsolidified upon standing.

21. 5-acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide

A 1.4M solution of methylmagnesium bromide in toluene and THF (3.88 mL,5.43 mmol) was added to a solution of2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acidmethoxy-methyl-amide (1.54 g, 4.17 mmol) in THF (20 mL) at −78° C. andunder nitrogen. The mixture was stirred at −78° C. for 1 hour and thenat room temperature for 16 hours. Then, a second portion ofmethylmagnesium bromide in toluene and THF (3.58 mL, 5.01 mmol) wasadded at 0° C. and the mixture was stirred at room temperature for 3hours. The mixture was diluted with a saturated solution of NH₄Cl andextracted with AcOEt. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; AcOEt in heptane 0/100to 50/50). The desired fractions were collected and the solventsevaporated in vacuo to yield5-acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (1.2 g,89% yield) as a white solid.

22. 1-(5-phenoxymethyl-2H-pyrazol-3-yl)-ethanone

5-Acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (0.1 g,0.32 mmol) was dissolved in a 1.25M solution of HCl in methanol (3.79mL) in a sealed tube and under nitrogen. The mixture was stirred at 65°C. for 24 hours, then basified with a saturated solution of NaHCO₃ andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; AcOEt in DCM 0/100 to40/60). The desired fractions were collected and the solvents evaporatedin vacuo to yield 1-(5-phenoxymethyl-2H-pyrazol-3-yl)-ethanone (55 mg,81% yield) as a white solid.

23. [2-(5-acetyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester

2-(2-tert-Butoxycarbonylamino)ethylbromide (0.54 g, 2.43 mmol) was addedto a suspension of 1-(5-phenoxymethyl-2H-pyrazol-3-yl)-ethanone (0.4 g,1.87 mmol) and K₂CO₃ (0.52 g, 3.74 mmol) in DMF (11 mL). The mixture wasstirred at room temperature for 16 hours and the solvent was evaporatedin vacuo. The crude product was purified by flash column chromatography(silica; AcOEt in heptane 0/100 to 50/50). The desired fractions werecollected and the solvents evaporated in vacuo to yield[2-(5-acetyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester (0.2 g, 30% yield) as a colourless oil.

24. 4-methyl-2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine

[2-(5-Acetyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester (0.2 g, 0.56 mmol) was dissolved in a 4M solution ofHCl in 1,4-dioxane (2.12 mL) under nitrogen. The mixture was stirred atroom temperature for 30 minutes and then the solvents evaporated invacuo. The residue was basified with a saturated solution of Na₂CO₃ andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo to yield4-methyl-2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (135 mg,99% yield) as a brown solid that was used without further purification.

25.rac-(4-fluoro-phenyl)-(2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

Sodium triacetoxyborohydride (20.8 mg, 0.093 mmol) was added to astirred solution of 2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine(15 mg, 0.062 mmol) in DCM (0.5 mL). The mixture was stirred at roomtemperature for 16 hours and then, 4-fluorobenzoyl chloride (0.011 mL,0.093 mmol) was added and the mixture stirred at room temperature for 1hour. The mixture was diluted with a saturated solution of Na₂CO₃ andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; AcOEt in DCM 0/100 to50/50). The desired fractions were collected and the solvents evaporatedin vacuo to yieldrac-(4-fluoro-phenyl)-(2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(19 mg, 84% yield) as a colourless oil that precipitated upon standing.¹H NMR (500 MHz, CDCl₃) δ ppm 1.56 (d, J=6.9 Hz, 3H), 3.59 (br. s., 1H),4.34 (br. s., 1H), 4.05-4.22 (m, 1H), 4.22-4.32 (m, 1H), 5.04 (s, 2H),5.58 (br. s., 1H), 6.15 (br. s., 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d,J=7.8 Hz, 2H), 7.10-7.20 (m, 2H), 7.27-7.34 (m, 2H), 7.40-7.49 (m, 2H).

26.2-(4-Fluoro-phenoxymethyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one anddiethyl oxalate using the methods described in the preceding examples 9(2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10(5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

27.(6R)-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and (1R)-2-hydroxy-1-methyl-ethyl-carbamic acidtert-butyl ester using the methods described in the preceding examples11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

28.(6S)-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and (1S)-2-hydroxy-1-methyl-ethyl-carbamic acidtert-butyl ester using the methods described in the preceding examples11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

29.(7*R)-7-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and (2S)-2-hydroxy-propyl-carbamic acid tert-butylester using the methods described in the preceding examples 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

30.(7*S)-7-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester and (2R)-2-hydroxy-propyl-carbamic acid tert-butylester using the methods described in the preceding examples 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

31.2-(2-tert-Butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester

2-(2-tert-butoxycarbonylamino)ethylbromide (3.55 g, 15.84 mmol) wasadded to a stirred suspension of5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (3.0 g, 12.18mmol) and K₂CO₃ (3.37 g, 24.36 mmol) in DMF (60 mL). The mixture wasstirred at room temperature for 72 hours and the solvent evaporated invacuo. The crude product was purified by flash column chromatography(silica; AcOEt in heptane 0/100 to 50/50). The desired fractions werecollected and the solvents were evaporated in vacuo to yield2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester (3.28 g, 69% yield) as a yellow oil.

32. [2-(5-Hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamicacid tert-butyl ester

A 1M solution of lithium aluminum hydride in THF (6.98 mL, 6.98 mmol)was added dropwise to a stirred solution of2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester (2.72 g, 6.98 mmol) in THF (47 mL) under N₂ at 0° C.The mixture was stirred at room temperature for 1 hour and diluted withAcOEt. Na₂SO₄.10H₂O was added at 0° C. and the mixture was stirred for15 minutes at this temperature, filtered through a pad of diatomaceousearth and then washed with additional AcOEt. The solvents wereevaporated in vacuo to yield[2-(5-hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester (2.5 g, 76% yield) as a white solid that was used inthe next step without further purification.

33. [2-(5-Formyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester

Manganese dioxide (6.94 g, 79.9 mmol) was added portionwise to a stirredsolution of[2-(5-hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester (2.5 g, 5.33 mmol) in 1,4-dioxane (45 mL). The mixturewas stirred at 100° C. for 16 hours and then filtered through a pad ofdiatomaceous earth. The solvents were evaporated in vacuo and the crudeproduct was purified by flash column chromatography (silica; AcOEt inheptane 0/100 to 50/50). The desired fractions were collected and thesolvents were evaporated in vacuo to yield[2-(5-formyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester (0.81 g, 44% yield) as a yellow solid.

34. 2-Phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from[2-(5-formyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acidtert-butyl ester using the method described in the preceding example 24(4-methyl-2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine).

35.rac-2-Phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

Trifluoroacetic acid (0.36 mL) was added to a stirred mixture of2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (0.43 g, 1.87 mmol)and potassium hydrogen fluoride (0.18 g, 2.34 mmol) in CH₃CN (3.7 mL)and DMF (0.4 mL) at 0° C. The mixture was stirred at 0° C. for 5minutes. Then Ruppert's reagent (0.83 mL, 5.61 mmol) was added and themixture was stirred at room temperature for 16 hours. The mixture wastreated with a saturated solution of Na₂CO₃, diluted with water andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; 7N solution of ammoniain methanol in DCM 0/100 to 30/70). The desired fractions were collectedand the solvents evaporated in vacuo to yieldrac-2-phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine(350 mg, 63% yield) as a yellow oil.

36. rac-2-(1-Phenoxy-ethyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

The compound was prepared from 3-phenoxy-butan-2-one and diethyl oxalateusing the methods described in the preceding examples 9(2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10(5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11(rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylicacid ethyl ester), 12(rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one),and 13(rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

37.(3-Chloro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone

N-chlorosuccinimide (21 mg, 0.16 mmol) was added to a solution of5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(50 mg, 0.14 mmol) in chloroform (1 mL). The mixture was stirred at 80°C. for 1 hour. Then the solvent was evaporated in vacuo and the crudeproduct was purified by flash column chromatography (silica; MeOH in DCM0/100 to 10/90). The desired fractions were collected and the solventsevaporated in vacuo. The product was repurified by flash columnchromatography (silica; AcOEt in heptane 0/100 to 50/50). The desiredfractions were collected and the solvents evaporated in vacuo. Theproduct was repurified by reverse phase HPLC (gradient from 80% of 0.1%solution of ammonium formate/ammonium hydroxide buffer pH 9 solution inwater and 20% CH₃CN to 0% of 0.1% solution of ammonium formate/ammoniumhydroxide buffer pH 9 solution in water and 100% CH₃CN) to yield(3-chloro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone(26 mg, 47% yield). C₂₀H₁₇ClFN₃O₂. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.05(br. s., 2H), 4.24 (br. s., 2H), 4.75 (br. s., 2H), 5.04 (s, 2H), 6.98(t, J=7.4 Hz, 1H), 7.03 (d, J=7.8 Hz, 2H), 7.17 (t, J=8.5 Hz, 2H), 7.30(dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).

38.(3-Fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone

N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (56mg, 0.16 mmol) was added to a solution of5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(50 mg, 0.14 mmol) in CH₃CN (2 mL). The mixture was stirred at 80° C.for 16 hours. Then the solvent was evaporated in vacuo and the crudeproduct was purified by flash column chromatography (silica; AcOEt inheptane 0/100 to 30/70). The desired fractions were collected and thesolvents evaporated in vacuo. The product was repurified by reversephase HPLC (gradient from 80% of 0.1% solution of ammoniumformate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9solution in water and 100% MeOH) to yield(3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone(11 mg, 20% yield). C₂₀H₁₇F₂N₃O₂. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.05(br. s., 2H), 4.20 (br. s., 2H), 4.79 (br. s., 2H), 5.05 (s, 2H), 6.97(t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 7.29(dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).

39.(4-Fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

N-iodosuccinimide (70 mg, 0.31 mmol) was added to a solution of5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine(0.1 g, 0.28 mmol) in chloroform (1 mL). The mixture was stirred at 65°C. for 1 hour. Then the solvent was evaporated in vacuo and the crudeproduct was purified by flash column chromatography (silica; AcOEt inheptane 0/100 to 50/50). The desired fractions were collected and thesolvents evaporated in vacuo to yield(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(0.13 g, 96% yield) as a white solid.

40.(4-Fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

Tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 0.014 mmol) was addedto a stirred solution of(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(0.13 g, 0.27 mmol), methylboronic acid (0.122 g, 2.04 mmol) andsaturated solution of Na₂CO₃ (2 mL) in 1,4-dioxane (4 mL) under N₂. Themixture was stirred at 100° C. for 21 hours and then the mixture wasdiluted with a saturated solution of Na₂CO₃ and extracted with DCM. Theorganic layer was separated, dried (MgSO₄), filtered and the solventsevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; AcOEt in heptane 0/100 to 70/30). The desiredfractions were collected and the solvents evaporated in vacuo. Theproduct was repurified by reverse phase HPLC (gradient from 80% of 0.1%solution of ammonium formate/ammonium hydroxide buffer pH 9 solution inwater and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammoniumhydroxide buffer pH 9 solution in water and 100% MeOH) to yield(4-fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(41 mg, 39% yield). C₂₁H₂₀FN₃O₂. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.00 (br.s., 3H), 3.98 (br. s., 2H), 4.22 (br. s., 2H), 4.73 (br. s., 2H), 5.02(s, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.02 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7Hz, 2H), 7.29 (dd, J=8.7, 7.3 Hz, 2H), 7.49 (dd, J=8.8, 5.3 Hz, 2H).

41.(3-Amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone

Tris(dibenzylideneacetone)dipalladium(0) (9.6 mg, 0.01 mmol) was addedto a stirred suspension of(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(50 mg, 0.1 mmol), sodium tert-butoxide (30 mg, 0.31 mmol) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19.6 mg, 0.031 mmol) intoluene (2 mL) in a sealed tube and under N₂. The mixture was stirred atroom temperature for 5 minutes and then benzophenone imine (0.035 mL,0.21 mmol) was added. The mixture was stirred at 100° C. for 2.5 hours.Then a 1M aqueous solution of HCl (3 mL) was added and the mixture wasstirred at room temperature for 16 hours. The mixture was diluted with asaturated solution of Na₂CO₃ and water and extracted with DCM. Theorganic layer was separated, dried (MgSO₄), filtered and the solventsevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; MeOH in DCM 0/100 to 6/94). The desiredfractions were collected and the solvents evaporated in vacuo. Thedesired product was triturated with diethyl ether to yield(3-amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone(18 mg, 47% yield) as a white solid. C₂₀H₁₉FN₄O₂₁H NMR (500 MHz, CDCl₃)δ ppm 1.53 (s, 1H), 2.86 (br. s., 1H), 3.99 (br. s., 2H), 4.18 (br. s.,2H), 4.70 (br. s., 2H), 5.08 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d,J=8.1 Hz, 2H), 7.15 (t, J=8.7 Hz, 2H), 7.30 (dd, J=8.4, 7.5 Hz, 2H),7.49 (dd, J=8.5, 5.3 Hz, 2H).

42.{5-[(4-Fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronicacid

A 1.3M solution of isopropylmagnesium chloride lithium chloride complexsolution (39 mL, 0.5 mmol) was added to a stirred solution of(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(0.2 g, 0.42 mmol) in THF (4 mL) at −78° C. and under N₂. The mixturewas stirred at −78° C. for 1 minute and then trimethyl borate (0.093 mL,0.84 mmol) was added. The mixture was stirred −78° C. for 30 minutes andat room temperature for 1 hour. The mixture was diluted with water andextracted with AcOEt. The organic layer was separated, dried (MgSO₄),filtered and the solvents evaporated in vacuo to yield{5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronicacid (0.21 g, 56% yield) as a yellow oil that was used in the next stepwithout further purification.

43.(4-Fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

A 2M aqueous solution of sodium hydroxide (0.53 mL, 1.06 mmol) was addedto a stirred solution of{5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronicacid (0.21 g, 0.53 mmol) and hydrogen peroxide (0.084 mL, 1.06 mmol) inTHF (5.3 mL) at 0° C. The mixture was stirred at room temperature for 16hours. Then the solvent was evaporated in vacuo and the crude productwas purified by flash column chromatography (silica; 7N solution ofammonia in methanol in DCM 0/100 to 5/95). The desired fractions werecollected and the solvents evaporated in vacuo to yield(4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(19 mg, 10% yield) as a colourless oil.

44.(4-Fluoro-phenyl)-(3-methoxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

Iodomethane (0.005 mL, 0.08 mmol) was added to a stirred suspension of(4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(19 mg, 0.052 mmol) and Cs₂CO₃ (0.034 g, 0.1 mmol) in DMF (0.5 mL). Themixture was stirred at room temperature for 45 minutes and the solventwas evaporated in vacuo. The crude product was purified by flash columnchromatography (silica; AcOEt in DCM 0/100 to 100/0). The desiredfractions were collected and the solvents evaporated in vacuo to yield(4-fluoro-phenyl)-(3-methoxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone(5 mg, 25% yield) as a colourless oil. C₂₁H₂₀FN₃O₃ ¹H NMR (400 MHz,CDCl₃) δ ppm 3.78 (br. s., 3H), 4.01 (br. s., 2H), 4.20 (br. s., 2H),4.80 (br. s., 2H), 5.02 (s, 2H), 6.93-7.00 (m, 1H), 7.03 (d, J=7.9 Hz,2H), 7.16 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.46-7.53 (m, 2H).

45. Additional Pyrazolo[1,5a]pyrazine Analogs

Compounds were synthesized having the structure:

wherein Ar¹ and Ar² were as described in Table II below. R^(1a), R^(1b),R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) were H unless asotherwise noted under “Other Substitutions” in Table II. The methodswere as described in the preceding examples with a reference examplemethod as noted in the table. Analytical data for the correspondinglynumbered compound in Table II is given in Table III, and opticalrotation values are given in Table IV. LCMS: [M+H]⁺ means the protonatedmass of the free base of the compound; R_(t) means retention time (inminutes); and Method refers to the LCMS method used.

TABLE II No. Ar¹ Ar² Other Substitutions* Reference Example 1

17 2

18 3

17 4

17 5

17 6

17 7

17 8

17 9

17 10

17 11

17 12

17 13

17 14

18 15

18 16

R^(4a) = CH₃ (racemic) 17 17

R^(5a) = CH₃ (racemic) 17 18

R^(4a) = CH₃ R^(4b) = CH₃ 17 19

R^(3a) = CH₃ (racemic) 25 20

18 21

18 22

18 23

18 24

18 25

17 26

18 27

18 28

18 29

18 30

17 31

18 32

18 33

18 34

18 35

18 36

18 37

18 38

17 39

17 40

R^(4a) = CH₃ (*R configuration) 17 41

R^(4a) = CH₃ (*S configuration) 17 42

R^(4a) = CH₃ (*S configuration) 18 43

R^(4a) = CH₃ (*S configuration) 17 44

R^(4a) = CH₃ (*S configuration) 18 45

R^(5a) = CH₃ (S configuration) 17 46

R^(5a) = CH₃ (R configuration) 17 47

R^(5a) = CH₃ (S configuration) 17 48

R^(5a) = CH₃ (R configuration) 17 49

R^(5a) = CH₃ (S configuration) 17 50

R^(5a) = CH₃ (R configuration) 17 51

R^(5a) = CH₃ (S configuration) 18 52

R^(5a) = CH₃ (R configuration) 18 53

R^(3a) = CF₃ (racemic) 17 54

R^(1a) = CH₃ (racemic) 17 55

R² = Cl 37 56

R² = F 38 57

R² = CH₃ 40 58

R² = NH₂ 41 59

R² = OCH₃ 44 *Note: “*R” and “*S” indicates that an enantiomericallypure compound was isolated with “R” and “S” arbitrarily assigned todistinguish the enantiomers; absolute configuration was not determined.

TABLE III LCMS No. M.p. (° C.) [M + H]⁺ R_(t) Method 1 106 352 3.34 2 2— 352 2.33 1 3 — 352 2.42 1 4 100.6 370 3.50 3 5 — 370 2.58 1 6 95.8 3702.42 1 7 — 370 2.50 2 8 — 370 2.48 1 9 159.2 352 2.49 1 10 — 370 2.60 111 79.7 388 2.61 1 12 126.9 370 2.55 1 13 112.7 388 2.66 1 14 125.4 3672.08 1 15 88.2 367 2.00 1 16 126.5 366 2.57 1 17 — 366 2.68 1 18 127.2380 4.35 4 19 89 352 2.42 1 20 114 371 2.07 1 21 >300 389 2.29 1 22 —367 1.91 1 23 >300 371 2.06 1 24 88 367 2.24 1 25 115.8 359 2.36 5 26109.8 377 2.56 5 27 60.3 377 2.57 5 28 133.3 377 2.51 5 29 60 369 2.13 530 101.5 377 3.28 2 31 76.8 395 2.71 5 32 >300 395 2.72 5 33 57.1 3952.69 5 34 — 354 1.87 1 35 105.5 368 2.05 1 36 282.6 354 1.61 1 37 104.5368 1.90 5 38 107.5 370 2.62 5 39 >300 370 2.66 5 40 — 366 2.83 5 41 —366 2.81 5 42 — 366 2.84 5 43 88.8 373 2.61 5 44 62.9 391 2.72 5 45 53.8366 2.77 5 46 >300 366 2.74 5 47 — 366 2.74 5 48 — 366 2.73 5 49 >300373 2.51 5 50 53.9 373 2.46 5 51 — 391 2.73 5 52 — 391 2.76 5 53 53.1420 3.36 5 54 — 366 2.79 5 55 136 386 3.12 5 56 — 370 4.54 6 57 158.5366 2.82 5 58 — 367 2.84 3 59 — 382 2.67 5

TABLE IV Wavelength Concentration Temp. No. α_(D) (°) (nm) w/v % Solvent(° C.) 40 −7.5 589 0.56 DMF 20 41 +15.3 589 0.47 DMF 20 42 +16.0 5890.59 DMF 20 43 +15.7 589 0.56 DMF 20 44 +21.5 589 0.53 DMF 20 45 −17.0589 0.80 DMF 20 46 +11.9 589 0.55 DMF 20 47 −53.4 589 1.25 DMF 20 48+20.4 589 0.54 DMF 20 49 −6.9 589 0.75 DMF 20 50 +6.8 589 0.53 DMF 20 51−10.3 589 0.47 DMF 20 52 +9.8 589 0.81 DMF 20

46. Generation of Human mGluR5 Stable Cell Line

Human mGluR5a cDNA in pCMV6-XL6 mammalian expression plasmid waspurchased from OriGene Technologies, Inc. (catalogue number SC326357)and subcloned into pcDNA3.1(−). Human embryonic kidney (HEK)293A cellswere then transfected with human mGluR5a pcDNA3.1(−) usingLipofectAmine2000 (Invitrogen) and monoclones were selected and testedfor functional response using a Ca²⁺ mobilization assay. Monoclones werenamed for the species (“H” for human) plus the location on the plate(e.g. “10H”).

47. Cell-Based Functional Assay

HEK cells transfected with the human mGluR5a receptor (H10H cell line)were plated at 15,000 cells/well in clear-bottomed poly-D-lysine-coatedassay plates (BD Falcon) in glutamate-glutamine-free growth medium andincubated overnight at 37° C. and 5% CO₂. The following day, the growthmedium was removed and the cells were washed with assay buffercontaining 1× Hank's balanced salt solution (Invitrogen, Carlsbad,Calif.), 20 mM HEPES, 2.5 mM probenecid, pH 7.4 and left with 20 μL ofthis reagent. Following this step, the cells were loaded with calciumindicator dye, fluo-4 AM, to a final concentration of 2 μM and incubatedfor 40-45 min at 37° C. The dye solution was removed and replaced withassay buffer. Cell plates were held for 10-15 min at room temperatureand were then loaded into the Functional Drug Screening System 6000(FDSS 6000, Hamamatsu, Japan).

After establishment of a fluorescence baseline for about 3 seconds, thecompounds of the present invention were added to the cells, and theresponse in cells was measured. 2.3 minutes later an EC₂₀ concentrationof the mGluR5 receptor agonist glutamate was added to the cells, and theresponse of the cells was measured for about 1.7 minutes. All testcompounds were dissolved and diluted to a concentration of 10 mM in 100%DMSO and then serially diluted into assay buffer for a 2× stock solutionin 0.6% DMSO; stock compounds were then added to the assay for a finalDMSO concentration of 0.3% after the first addition to the assay well.Calcium fluorescence measures were recorded as fold over basalfluorescence; raw data was then normalized to the maximal response toglutamate. Potentiation of the agonist response of the mGluR5 receptorin the present invention was observed as an increase in response tosubmaximal concentrations of glutamate in the presence of compoundcompared to the response to glutamate in the absence of compound.

48. Data Analysis

The concentration-response curves of compounds of the present invention,obtained in the presence of EC₂₀ of mGluR5 receptor agonist glutamate todetermine positive allosteric modulation, were generated using MicrosoftExcel with IDBS XLfit add-ins. The raw data file containing all timepoints was used as the data source in the analysis template. This wassaved by the FDSS as a tab-delimitted text file. Data were normalizedusing a static ratio function (F/F₀) for each measurement of the total350 values per well divided by each well's initial value. Data was thenreduced as to peak amplitudes (Max−Initial Min) using a time range thatstarts approximately 1 second after the glutamate EC₂₀ addition andcontinues for approximately 40 seconds. This is sufficient time tocapture the peak amplitude of the cellular Calcium response. Individualamplitudes were expressed as % E_(Max) by multiplying each amplitude by100 and then dividing the product by the mean of the amplitudes derivedfrom the glutamate EC_(Max)-treated wells. pEC₅₀ values for testcompounds were generated by fitting the normalized values versus the logof the test compound concentration (in mol/L) using a 4 parameterlogistic equation where none of the parameters were fixed. Each of thethree values collected at each concentration of test compound wereweighted evenly. Individual values falling outside the 95% predictionlimits of the curve fit were automatically excluded from the fit. Acompound was designated as a positive allosteric modulator if thecompound showed a concentration-dependent increase in the glutamate EC₂₀addition. % E_(Max) for compounds may be estimated using the resultingcorresponding parameter value determined using the curve fit or bytaking an average of the overall maximum response at a singleconcentration. These two methods are in good agreement for curves with aclear plateau at the high concentration range. For data that show anincrease in the EC₂₀ response, but, do not hit a plateau, the average ofthe maximum response at a single concentration is preferred. Forconsistency purposes across the range of potencies observed, all Emaxvalues reported in this application are calculated using the maximumaverage response at a single concentration. The % E_(Max) value for eachcompound reported in this application is defined as the maximum % effectobtained in a concentration-response curve of that compound expressed asa percent of the response of a maximally effect concentration ofglutamate. Table I above shows the pharmacological data obtained for aselected set of compounds. For compounds showing a lower potency (e.g.as indicated by a lack of a plateau in the concentration responsecurve), but with a greater than a 20% increase in glutamate response, apotency of >10 μM (pEC₅₀<5) was estimated.

49. Prospective In Vivo Effects

Generally clinically relevant antipsychotic agents (both typical andatypical) display efficacy in preclinical behavior challenge models. Invivo effects of the compounds described in the preceding examples areexpected to be shown in various behavioural challenge models known tothe skilled person, such as Amphetamine-, Phencyclidine (PCP)-inducedhyperlocomotion in rodents and other models, such as NMDA receptorantagonists for example MK801.

In vivo effects of compounds having a structure represented by aformula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, are expectedto show activity in in various behavioural challenge models known to theskilled person, such as Amphetamine-, Phencyclidine (PCP)-inducedhyperlocomotion in rodents and other models, such as NMDA receptorantagonists for example MK801.

50. In Vivo Effects of(4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanonein the Rat Hyperlocomotion Assay

Locomotor activity was assessed as mean distance traveled (cm) instandard 16×16 photocell testing chambers measuring 43.2 cm(Length)×43.2 cm (Width)×30.5 cm (Height) (Med Associates, St. Albans,Vt.). Animals were habituated to individual activity chambers for atleast 30 min prior to drug administration. Following administration ofdrug or vehicle, activity was recorded for a 90 minute time period. Datawas expressed as the mean (±SEM) distance traveled recorded in 5 minintervals over the test period. The data was analyzed using repeatedmeasures analysis of variance (ANOVA) followed by post-hoc testing usingDunnett's test, when appropriate. A difference was consideredsignificant when p≦0.05.

Amphetamine sulfate was obtained from Sigma (Cat#A5880-1G; St. Louis,Mo.) and 10 mg was dissolved in 10 ml of water. Test compound,(4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone,was formulated in a volume of 10 ml with an amount of drug appropriateto the dosage indicated. The appropriate amount of compound was mixedinto a 20% 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) solution. Thesolution was formulated so that animals were injected with a volumeequal to about 10× body weight. The mixture was then ultrahomogenized onice for 2-3 minutes using the Dismembrator (Fisher Scientific Model150T). Then the pH was checked using 0-14 EMD strips and adjusted to apH of 6-7 if necessary. The mixture was then vortexed and stored in awarm sonication bath until time to be injected. Animals wereadministered samples of the following: (a) Amphetamine sulfate, 1 mg/kg,administered subcutaneously; (b)(4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone,dose as indicated in FIG. 4, was administered by oral gavage; and (c)vehicle, pH 7, administered subcutaneously and intraperitoneally.

The study was carried out using male Sprague-Dawley rats weighing 225g-275 g, between 2-3 months old (Harlan, Inc., Indianapolis, Ind.), wereused. They were kept in the animal care facility certified by theAmerican Association for the Accreditation of Laboratory Animal Care(AALAC) under a 12-hour light/dark cycle (lights on: 6 a.m.; lights off:6 p.m.) and had free access to food and water. The experimentalprotocols performed during the light cycle were approved by theInstitutional Animals Care and Use Committee of Vanderbilt Universityand conformed to the guidelines established by the National ResearchCouncil Guide for the Care and Use of Laboratory Animals.

The animals were habituated in Smart Open Field locomotor activity testchambers (Hamilton-Kinder, San Diego, Calif.) with 16×16 photobeams toautomatically record locomotor activity for 30 min and then dosed withvehicle or test compound. The rats were then placed into cages. At 60min, all rats were injected subcutaneously with 1 mg/kg amphetamine orvehicle and then monitored for an additional 60 min. Animals aremonitored for a total of 120 minutes. Data are expressed as changes inambulation defined as total number of beam breaks per 5 min periods.

The data for the dose-response studies were analyzed by a between-groupanalysis of variance. If there was a main effect of dose, then each dosegroup was compared with the vehicle amphetamine group. The calculationswere performed using JMP IN 8 (SAS Institute, Cary, N.C.) statisticalsoftware and graphed using SigmaPlot9 (Saugua, Mass.). Results forreversal of amphetamine-induced hyperlocomotion by(4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanoneare shown in FIG. 4. The following abbreviations are used: (a)“compound” refers to(4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone(“FPPPM”); (b) subcutaneous administration of compound is indicated by“sc”; (c) oral gavage administration is indicated by “po”; and (d)amphetamine sulfate is indicated as “amph”. The time of administrationof amphetamine sulfate is indicated in FIG. 4 by “Amph” and thecorresponding arrow. The vehicle for FPPPM is 20% wt/v HP-β-CD, and thevehicle for amphetamine is sterile water.

51. Prophetic Pharmaceutical Composition Examples

“Active ingredient” as used throughout these examples relates tocompound having a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or pyridonyl and has 0-3 substituents selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4alkyl; wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of R^(3a)and R^(3b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(4a) andR^(4b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein R^(4a) and R^(5a)are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl, or Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; or a pharmaceutically acceptable salt thereof, thesolvates, polymorphs, hydrates and the stereochemically isomeric formsthereof. The following examples of the formulation of the compounds ofthe present invention in tablets, suspension, injectables and ointmentsare prophetic. Typical examples of recipes for the formulation of theinvention are as given below.

a. Tablets

A tablet can be prepared as follows:

Component Amount Active ingredient 5 to 50 mg Di-calcium phosphate 20 mgLactose 30 mg Talcum 10 mg Magnesium stearate 5 Potato starch add tomake total weight 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

b. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

c. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

d. Ointment

An ointment can be prepared as follows:

Component Amount Active ingredient 5 to 1000 mg Stearyl alcohol 3 gLanoline 5 g White petroleum 15 g Water add to make total weight 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1-11. (canceled)
 12. A method for the treatment of a neurological and/orpsychiatric disorder associated with glutamate dysfunction in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl, or Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, orpyrazinyl, and has 0-3 substituents selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein each of R^(1a) and R^(1b) is independently selected fromhydrogen, C1-C4 alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl;wherein R² is selected from hydrogen, halogen, cyano, —NH₂, C1-C4 alkyl,monohalo C1-C4 alkyl, C1-C4 alkoxy, and polyhalo C1-C4 alkyl; whereineach of R^(3a) and R^(3b) is independently selected from hydrogen, C1-C4alkyl, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalentlybonded and, together with the intermediate carbon, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(4a) and R^(4b) is independently selected from hydrogen, C1-C4 alkyl,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bondedand, together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen, C1-C4 alkyl, monohaloC1-C4 alkyl, and polyhalo C1-C4 alkyl, or are covalently bonded and,together with the intermediate carbon, comprise an optionallysubstituted 3- to 7-membered spirocycloalkyl; and wherein Ar² is phenylwith 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl, or Ar² ispyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and has 0-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; or a pharmaceuticallyacceptable salt thereof.
 13. The method of claim 12, wherein the mammalis a human.
 14. The method of claim 12, wherein the mammal has beendiagnosed with a need for treatment of the disorder prior to theadministering step.
 15. The method of claim 12, wherein the disorder isa neurological and/or psychiatric disorder associated with mGluR5dysfunction.
 16. The method of claim 12, wherein the disorder isselected from dementia, delirium, amnestic disorders, age-relatedcognitive decline, schizophrenia, psychosis including schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, substance-related disorder, movementdisorders, epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. 17-20. (canceled)
 21. The method ofclaim 12, further comprising the step of identifying a mammal in need oftreatment of the disorder.
 22. The method of claim 12, wherein R^(1a),R^(1b), R², R^(3a), and R^(3b) are each hydrogen.
 23. The method ofclaim 12, wherein Ar¹ is phenyl.
 24. The method of claim 12, wherein Ar¹is phenyl with 1-3 substituents selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.25. The method of claim 12, wherein Ar¹ is pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or pyridonyl.
 26. The method of claim 12,wherein Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, orpyridonyl and has 1-3 substituents selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl.27. The method of claim 12, wherein the compound has a structurerepresented by a formula:


28. The method of claim 12, wherein the compound has a structurerepresented by a formula:


29. The method of claim 12, wherein the compound has a structurerepresented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; and wherein Ar² is phenyl with 0-3 substituents selectedfrom halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl,and polyhalo C1-C4 alkyl.
 30. The method of claim 12, wherein thecompound has a structure represented by a formula:

wherein Ar¹ is phenyl with 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl; and wherein Ar² is pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, or pyridonyl and has 0-3 substituents selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhaloC1-C4 alkyl.
 31. The method of claim 12, wherein the compound exhibitspotentiation of mGluR5 response to glutamate in human embryonic kidneycells transfected with rat mGluR5 with an EC₅₀ of less than about 10,000nM.